9-aminomethyl minocycline compounds and uses thereof

ABSTRACT

Methods and compositions for using a tetracycline compound to treat bacterial infections are described. In one embodiment, for example, the invention provides a method of treating a subject for an infection, comprising administering to said subject an effective amount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, such that said subject is treated, wherein the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered orally at a dose of about 450 mg per day for two consecutive days, then at a dose of about 300 mg per day for 5 or more days.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/667,683, filed onAug. 3, 2017, which claims the benefit of the filing date under 35U.S.C. § 119(e) to U.S. Provisional Application No. 62/370,527, filed onAug. 3, 2016; 62/514,479, filed on Jun. 2, 2017; and 62/532,454, filedon Jul. 14, 2017, the entire contents of each of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The development of the tetracycline antibiotics was the direct result ofa systematic screening of soil specimens collected from many parts ofthe world for evidence of microorganisms capable of producingbactericidal and/or bacteriostatic compositions. The first of thesenovel compounds was introduced in 1948 under the name chlortetracycline.Two years later, oxytetracycline became available. The elucidation ofthe chemical structure of these compounds confirmed their similarity andfurnished the analytical basis for the production of a third member ofthis group in 1952, tetracycline. A new family of minocycline compounds,without the ring-attached methyl group present in earlier tetracyclines,was prepared in 1957 and became publicly available in 1967; andminocycline was in use by 1972.

Later research efforts have focused on developing new tetracyclineantibiotic compositions effective under varying therapeutic conditionsand routes of administration. New tetracycline analogues have also beeninvestigated which may prove to be equal to or more effective than theoriginally introduced minocycline compounds. Examples include U.S. Pat.Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280;3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patentsare representative of the range of pharmaceutically active tetracyclineand tetracycline analogue compositions.

Historically, soon after their initial development and introduction, thetetracyclines were found to be highly effective pharmacologicallyagainst rickettsia; a number of Gram-positive and Gram-negativebacteria; and the agents responsible for lymphogranuloma venereum,inclusion conjunctivitis, and psittacosis. Hence, tetracyclines becameknown as “broad spectrum” antibiotics. With the subsequent establishmentof their in vitro antimicrobial activity, effectiveness in experimentalinfections, and pharmacological properties, the tetracyclines as a classrapidly became widely used for therapeutic purposes.

However, this widespread use of tetracyclines for both major and minorillnesses and diseases led directly to the emergence of resistance tothese antibiotics even among highly susceptible bacterial species bothcommensal and pathogenic (e.g., pneumococci and Salmonella). The rise oftetracycline-resistant organisms has resulted in a general decline inuse of tetracyclines and tetracycline analogue compositions asantibiotics of choice. In addition, other antibacterial agents have alsobeen over used, creating strains of multiple drug resistant (MDR)bacteria.

Over the past decade, Gram-positive bacteria with multi-drug resistanceto a diverse range of antibiotics have emerged as a major treatmentchallenge. Two developments raise the specter that currently availableantibiotics may become even less useful for treatment of infectionscaused by Gram-positive organisms. The first is the emergence ofvancomycin resistance in Enterococcus species (spp.) and the subsequenttransfer of those resistance elements to Staphylococcus aureus. Althoughvancomycin-resistant Staphylococcus aureus have not becomeepidemiologically significant, their very existence raises concernbecause vancomycin has been the agent of choice for infections caused byresistant Gram-positive pathogens.

The second important development is the appearance of community-acquiredmethicillin-resistant Staphylococcus aureus (MRSA). These strains areincreasingly becoming multi-drug resistant over time. In many areas ofthe world, MRSA infections represent the majority of sporadicstaphylococcal infections with community-onset. These strains also havebeen associated with numerous outbreaks of localized (skin and skinstructure) and invasive (bacteremic) infections.

Other than the general need for effective antibacterial agents for thetreatment of bacterial infections, there is also a specific need fororal antibiotic therapies.

Compared to IV administration, oral antibiotic therapies can beadvantageous because they can eliminate the requirement for hospitalvisit and/or stay, thus reducing the overall cost of treatment, limitinga patient's exposure to secondary infection in the hospital setting, andincreasing the availability of the treatment in areas where hospitalsare less accessible or unavailable, particularly in the remote oreconomically underdeveloped areas or parts of the world.

Unfortunately, due to the rise of antibiotic resistance, use of olderagents has led to increasing hospital visits, which in turn increasespatients' chances of becoming infected by other bacteria.

Thus there is still a need for a new, effective oral antibacterialagent, particularly oral only dosing regimens, for treating, forexample, a bacterial skin or skin structure infection, such as ABSSSI.ABSSSI alone is responsible for more than 750,000 hospitalizations peryear (based on the latest data in 2011), representing a 17.3% increasein hospitalized ABSSSI patients from 2005-2011.

SUMMARY OF THE INVENTION

One aspect of the invention provides a method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising orally administering to the subject an effectiveamount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline (also knownas Omadacycline or OMC) or a salt thereof, such that the subject istreated, wherein the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineis administered as once-daily oral dose of 450 mg or 600 mg for 5 ormore days.

In certain embodiments, the once-daily oral dose is 450 mg, administeredfor 5 or more consecutive days.

In certain embodiments, the once-daily oral dose is 600 mg, administeredfor 5 or more consecutive days.

A related aspect of the invention provides a method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising orally administering to the subject an effectiveamount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a saltthereof, such that the subject is treated, wherein the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered asonce-daily oral dose of 300 mg, for 5, 6, 7, or 8 consecutive days.

Another related aspect of the invention provides a method of treating ahuman subject in need of treatment for a bacterial skin or skinstructure infection, comprising orally administering to the subject aneffective amount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineor a salt thereof, such that the subject is treated, wherein the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered withan oral loading dose, followed by once-daily oral doses of 300-600 mg(e.g., 300 mg, 450 mg, or 600 mg) for 5 or more days.

In certain embodiments, the oral loading dose consists essentiallyof/consists of one oral dose of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 24 hours before the first ofthe once-daily oral doses of 300 mg, 450 mg, or 600 mg.

In certain embodiments, the oral loading dose consists essentiallyof/consists of one oral dose of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 24 hours before the first ofthe once-daily oral doses of 300 mg, 450 mg, or 600 mg. In certainembodiments, the oral loading dose consists essentially of/consists oftwo oral doses of 300 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 12 hours and 24 hours,respectively, before the first of the once-daily oral doses of 300 mg,450 mg, or 600 mg.

In certain embodiments, the oral loading dose consists essentiallyof/consists of two oral doses of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 12 hours and 24 hours,respectively, before the first of the once-daily oral doses of 300 mg,450 mg, or 600 mg.

In certain embodiments, the oral loading dose consists essentiallyof/consists of two oral dose of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 24 hours and 48 hours,respectively, before the first of the once-daily oral doses of 300 mg,450 mg, or 600 mg.

In certain embodiments, the oral loading dose consists essentiallyof/consists of two oral dose of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, administered 24 hours and 48 hours,respectively, before the first of the once-daily oral doses of 300 mg,450 mg, or 600 mg.

In another aspect, the invention provides a method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising orally administering to the subject an effectiveamount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a saltthereof, such that the subject is treated, wherein the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredorally at a dose of about 450 mg per day for two consecutive days, thenat a dose of about 300 mg per day for 5 or more days.

In certain embodiments, the bacterial skin or skin structure infectionis wound infection, cellulitis/erysipelas, major abscess,furuncles/boils, carbuncle, Staphylococcal scalded skin syndrome (SSSS),or ecthyma.

In certain embodiments, the bacterial skin or skin structure infectionis Acute Bacterial Skin and Skin Structure Infection (ABSSSI), such ascommunity-acquired ABSSSI.

In certain embodiments, the ABSSSI is greater than or equal to 75 cm² intotal surface area of contiguous involved tissue.

In certain embodiments, he ABSSSI comprises wound infection,cellulitis/erysipelas, and/or major abscess.

In certain embodiments, the bacterial skin or skin structure infectionis a result of skin injury including but not limited to trauma, asurgical procedure, or IV drug use.

In certain embodiments, the bacterial skin or skin structure infectionis a result of vascular insufficiency or edema.

In certain embodiments, the human subject is administered9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline under fastingcondition.

In certain embodiments, the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered once per day (e.g., each oraldose is administered about 24 hours apart).

In certain embodiments, the subject is treated up to and including about14 days, up to and including about 10 days, up to and including about 9days, up to and including about 8 days, or up to and including about 7days, up to and including about 5 days, such that the subject istreated.

In certain embodiments, the subject is treated for 7-10 days.

In certain embodiments, the subject is treated for 8 days.

In certain embodiments, the salt is a tosylate salt.

In certain embodiments, the bacterial skin or skin structure infectionis known or suspected to be caused by Gram-positive pathogens. Forexample, the Gram-positive pathogens may include Staphylococcus aureus,Staphylococcus lugdunensis, Streptococcus species, Streptococcusagalactiae, Streptococcus mitis, Enterococcus species (Enterococcusfaecalis (such as VRE or VSE), or Enterococcus faecium (such as VRE orVSE)), Streptococcus anginosus group (S. anginosus, S. constellatus, andS. intermedius, that is beta-, alpha- or non-hemolytic), Viridans groupStreptococci (VGS), Clostridium perfringens, Finegoldia magna, or acombination thereof. The Staphylococcus aureus may bemethicillin-resistant Staphylococcus aureus (MRSA), ormethicillin-susceptible Staphylococcus aureus (MSSA). The Streptococcusspecies may include Streptococcus anginosus group. The Streptococcusspecies may include beta-hemolytic Streptococci or S. anginosus. TheStreptococcus species may include non-hemolytic Streptococci or S.intermedius. The Streptococcus species may include alpha-hemolyticStreptococci or S. constellatus. The Enterococcus species may includeEnterococcus faecalis (VSE). The Streptococcus species may includeStreptococcus pyogenes.

In certain embodiments, the bacterial skin or skin structure infectionis known or suspected to be caused by Gram-negative pathogens. Forexample, the Gram-negative pathogens may include Enterobacter cloacae,Escherichia coli, Klebsiella pneumoniae, Prevotella denticola,Prevotella melaninogenica, or a combination thereof.

In certain embodiments, the bacterial skin or skin structure infectionis known or suspected to be caused by any of the preceding Gram-positiveand Gram-negative pathogens, or a combination thereof.

In certain embodiments, gastrointestinal (GI) adverse events (AEs)associated with treatment are predominantly mild. In certainembodiments, GI adverse events (AEs) associated with treatment do notresult in discontinuation of therapy.

In certain embodiments, AUC₀₋₂₄ after the first two doses of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof isabout 10,000 ng*h/mL.

In certain embodiments, each dose of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or salt thereof is administered as 150 mgtablets.

In certain embodiments, the method has a clinical success rate of about70-100%. For example, the clinical success rate may be about 80-100%,about 79-98%, about 79-94%, about 84-98%, about 80-88%, or about 84-89%.

In certain embodiments, the clinical success rate is observed at 48-72hours after the first oral dose, and is about 79-94%, or about 84-89%,or about 87.5%. In certain embodiments, the ABSSSI consists essentiallyof wound infection, and the clinical success rate is about 84-94%, orabout 89%. In certain embodiments, the ABSSSI consists essentially ofcellulitis/erysipelas, and the clinical success rate is about 74-84%, orabout 79%. In certain embodiments, the ABSSSI consists essentially ofmajor abscess, and the clinical success rate is about 90-98%, or about94%.

In certain embodiments, the clinical success rate is overall clinicalsuccess rate observed at about 7-14 days after the last dose oftreatment, and is about 79-98%, about 75-95%, about 79-89%, 84%, about95-100%, or about 98%. In certain embodiments, the ABSSSI consistsessentially of wound infection, and the overall clinical success rate isabout 80-85%, or is about 82-83%. In certain embodiments, the ABSSSIconsists essentially of cellulitis/erysipelas, and the overall clinicalsuccess rate is about 85-91%, about 87-88%, or is about 88%. In certainembodiments, the ABSSSI consists essentially of major abscess, and theoverall clinical success rate is about 80-88%, or about 84%.

In a related aspect, the invention provides a method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising administering to the subject an effective amountof 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that the subject is treated, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered intravenously (i.v.) at adose of about 150 mg per day for two consecutive days, then at a dose ofabout 300 mg per day orally for 5 or more days. Because of the knownbioequivalence established between oral and i.v. doses for9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, the 150 mg i.v. doseis considered bioequivalence of 450 mg oral dose. Thus the alternativeembodiment in this aspect of the invention is considered to beencompassed within the scope of the instant invention.

It should be understood that any one embodiment can be combined with anyone or more other embodiments, including those embodiments disclosedonly in the examples or only under one aspect of the invention, unlessthe combination is inappropriate or expressly disclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows plasma concentration-time curve for a single oral 300 mgdose of omadacycline.

FIG. 2 shows PK data for a dosing regimen, in which 100 mg ofomadacycline is administered i.v. BID (twice a day, administered 12 hrsapart) for 1 day, followed by 100 mg i.v. per day.

FIG. 3 shows PK data for a dosing regimen, in which 450 mg ofomadacycline is administered p.o. QD (once a day) for 2 days, followedby 300 mg p.o. per day.

FIG. 4 shows PK data for a dosing regimen, in which 600 mg ofomadacycline is administered p.o. QD (once a day) for 2 days, followedby 300 mg p.o. per day.

FIG. 5 shows plasma concentration versus time curves of omadacyclineafter oral administration. Mean (±SD) plasma concentrations ofomadacycline versus time are shown by omadacycline dose (300, 450, or600 mg) for the pharmacokinetic population. Oral omadacycline doses wereadministered at time 0 on each of 5 consecutive days of dosing in eachof 3 periods. Blood samples were collected for PK analysis on Day 1(left panel) and Day 5 (right panel). Data was pooled by omadacyclinedose for all subjects regardless of the period in which they received aparticular dose.

FIG. 6 shows that Omadacycline demonstrated statistical non-inferiority(10% margin) relative to linezolid, for early clinical response (ECR) inthe mITT (modified Intent To Treat) population (see the pair of bars onthe left) (FDA Primary Endpoint); and for clinical success at the PTE(Post Treatment/Therapy Evaluation), in both the mITT PTE population(see the middle pair of bars) and the CE-PTE (Clinically Evaluablepopulation at the PTE) population (see the right pair of bars) (EMACo-primary Endpoints).

DETAILED DESCRIPTION OF THE INVENTION 1. Overview

Omadacycline (9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline) isvery active in vitro against most Gram-positive pathogens. For example,it has been shown to be effective in treating complicated Skin and SkinStructure Infections (see U.S. Pat. No. 9,265,740, incorporated hereinby reference). It also exhibits activity against atypical pathogens(e.g., Legionella spp.), and some anaerobic and Gram-negative pathogens.The drug is active against strains expressing both mechanisms oftetracycline resistance as well as strains that are resistant tocurrently available antibiotics, including methicillin, vancomycin,erythromycin, and ciprofloxacin. Omadacycline also has demonstratedactivity against the most common ABSSSI pathogens, including isolatesresistant to standards of care.

Omadacycline has been developed for both i.v. and p.o. (oral)administration. To date, over 1000 subjects have received one or bothformulations in completed clinical studies.

In completed Phase 1 studies, single i.v. doses up to 600 mg and singlep.o. doses up to 600 mg have been investigated. Multiple i.v. doses of100 mg once daily and 200 mg once daily for up to 14 and 7 consecutivedays, respectively, have been investigated. Multiple p.o. doses of 200mg once daily and 300 mg once daily for up to 10 consecutive days havebeen investigated. In addition, multiple p.o. doses of 450 mg once dailyand 600 mg once daily for 5 consecutive days have also beeninvestigated.

In a Phase 2 study, 219 subjects with complicated skin and skinstructure infections (cSSSI) were treated with omadacycline (n=111) orlinezolid (n=108); treatment was initiated with i.v. administration (100mg per day), with switch to p.o. therapy (200 mg per day) at thediscretion of the investigator. In this study the total duration ofstudy treatment was a mean of 10 and maximum of 20 days.

In a sponsor terminated Phase 3 study of similar design, 140 subjectswith cSSSI were treated with omadacycline (n=68) or linezolid (n=72) fora mean of 10 and maximum of 20 days for omadacycline and 22 days forlinezolid. Patients were initially treated with study drug omadacyclineIV (100 mg per day), and then switched to oral therapy at the discretionof the Investigator (300 mg per day). The expected duration of IVtreatment was 4-7 days; the expected total duration of treatment (IV andoral) was up to 14 days. The study was double-blinded during the IVtreatment phase and Evaluator-blinded during the oral treatment phase.

In a recently completed Phase 3 study comparing omadacycline andlinezolid for the treatment of adults with ABSSSI, subjects startedtherapy with omadacycline 100 mg i.v. every 12 hours (q12h) for 2 dosesthen 100 mg i.v. every 24 hours (q24h), or linezolid 600 mg i.v. q12h.Subjects could be switched to oral therapy (omadacycline 300 mg q24h orlinezolid 600 mg q12h) after a minimum of 3 days of i.v. therapy; thetotal treatment duration was 7-14 days. Study results showed thatomadacycline was non-inferior to linezolid. In the FDA primary analysispopulation (defined as ITT subjects without a sole Gram-negativepathogen(s) at screening, total N=627) for omadacycline versuslinezolid, respectively, clinical success based on a reduction of lesionsize at 48-72 hours after the first dose was 84.8% versus 85.5% (95%confidence interval [CI]: −6.3, 4.9); clinical success based oninvestigator's assessment of clinical response at 7-14 days after thelast dose was 86.1% versus 83.6% (CI: −3.2, 8.2). Omadacycline was welltolerated: treatment-emergent adverse events (TEAEs) were reported in48.3% versus 45.7%; serious TEAEs in 3.4% versus 2.5% anddiscontinuation due to TEAE in 1.9% versus 2.2% of omadacycline andlinezolid treated subjects, respectively.

In all the above studies, however, a portion of the dosing regimenrequires i.v. administration of omadacycline, thus necessitatinghospital visit and/or stay, or time spent in an outpatient infusioncenter. In an effort to develop an effective oral only dosing regimenthat eliminates hospital visits, thus particularly desirable fortreating community-acquired bacterial skin or skin structure infections(e.g., ABSSSI or cSSSI), an initial oral only dosing regimen wasdeveloped, in which a human subject in need of treatment for a bacterialskin or skin structure infection is given omadacycline orally, at a dosecomparable to that used in the recently completed Phase 3 study: i.e.,about 300 mg BID (twice daily, 300 mg each time, administered about 12hours apart) for one day, followed by a dose of about 300 mg per day fora total of 7-14 days. Of note, a prior Phase 1 study has demonstratedthat a 300 mg oral dose using the tablet formulation of omadacycline isbioequivalent (based on serum AUC) to a 100 mg i.v. dose.

Omadacycline was found to have a significant food effect, in that foodconsumption has a significant impact on the oral bioavailability oforally administered 300 mg dose of omadacycline. See Example 1. A PKstudy in healthy volunteers showed that, compared with a fasted dose,bioavailability was reduced by 15% to 17% for a nondairy meal 4 hoursbefore dosing, 40% to 42% for a nondairy meal 2 hours before dosing, and59% to 63% for a dairy meal 2 hours before dosing. Thus, the effect offood was more pronounced when a high-fat meal was consumed closer todosing and when dairy was included in the meal. Based on this result,oral omadacycline should be administered at least 6 hours following ameal in order to achieve maximum bioavailability for the oral dosedesigned to achieve therapeutic efficacy.

This food effect poses a significant patient compliance challenge,particularly when two oral doses are to be administered in one day atthe beginning of the dosing regimen.

Preliminary results of a Phase 1 study showed that oral dosing regimensof 300 mg QD (q24h) and 450 mg QD (q24h) had similar and favorabletolerability profiles. In addition, PK results and PK modeling indicatethat a regimen of 450 mg p.o. QD (q24h) for 2 doses followed by 300 mgp.o. QD (q24h) achieves approximately the same steady stateconcentrations within the same time frame as a dosing regimen startingwith 300 mg p.o. q12h for 2 doses, then 300 mg p.o. QD (q24h). In bothregimens, a total of 900 mg oral omadacycline is administered over thefirst 2 days. See Example 2.

Thus in one aspect, the invention provides a method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection.

In a 1^(st) embodiment, the method comprises orally administering to thesubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that the subject istreated, wherein the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineis administered as once-daily oral dose of 450 mg or 600 mg for 5 ormore days.

In a 2^(nd) embodiment, the method comprises orally administering to thesubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that the subject istreated, wherein the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineis administered as once-daily oral dose of 300 mg, for 5, 6, 7, or 8consecutive days.

In a 3^(rd) embodiment, the once-daily oral dose of the 1^(st)embodiment is 450 mg, administered for 5 or more consecutive days.

In a 4^(th) embodiment, the once-daily oral dose of the 1^(st)embodiment is 600 mg, administered for 5 or more consecutive days.

In a 5^(th) embodiment, the method comprises orally administering to thesubject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that the subject istreated, wherein the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocyclineis administered with an oral loading dose (e.g., a dose higher thanonce-daily oral dose of 300 mg), followed by once-daily oral doses of300-600 mg (e.g., 300 mg, 450 mg, or 600 mg) for 5 or more days.

In a 6^(th) embodiment, the oral loading dose of the 5^(th) embodimentconsists essentially of/consists of one oral dose of 600 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 24hours before the first of the once-daily oral doses of 300, 450, or 600mg.

In a 7^(th) embodiment, the oral loading dose of the 5^(th) embodimentessentially of/consists of one oral dose of 450 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 24hours before the first of the once-daily oral doses of 300, 450, or 600mg.

In an 8^(th) embodiment, the oral loading dose of the 5^(th) embodimentconsists essentially of/consists of two oral doses of 300 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 12hours and 24 hours, respectively, before the first of the once-dailyoral doses of 300 mg, 450 mg, or 600 mg.

In a 9^(th) embodiment, the oral loading dose of the 5^(th) embodimentconsists essentially of/consists of two oral doses of 450 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 12hours and 24 hours, respectively, before the first of the once-dailyoral doses of 300 mg, 450 mg, or 600 mg.

In a 10^(th) embodiment, the oral loading dose of the 5^(th) embodimentconsists essentially of/consists of two oral dose of 600 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 24hours and 48 hours, respectively, before the first of the once-dailyoral doses of 300 mg, 450 mg, or 600 mg.

In a 11^(th) embodiment, the oral loading dose of the 5^(th) embodimentconsists essentially of/consists of two oral dose of 450 mg of the9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, administered 24hours and 48 hours, respectively, before the first of the once-dailyoral doses of 300 mg, 450 mg, or 600 mg.

In a 12^(th) embodiment, the method comprises orally administering tothe subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (omadacycline) or a salt thereof, such thatthe subject is treated, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally, at a dose of about450 mg per day for two consecutive days, then at a dose of about 300 mgper day for 5 or more days, e.g., for a total treatment duration of 7-14days.

As used herein, “bacterial skin and skin structure infection” is aninfection of skin and associated soft tissues, such as loose connectivetissue and mucous membranes. The pathogen involved in the bacterial skinand skin structure infection is a bacterial species. Such infectionsoften requires treatment by antibiotics, such as the subject9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.

In a 13^(th) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-12^(th) embodiments is wound infection,cellulitis/erysipelas, major abscess, furuncles/boils, carbuncle,Staphylococcal scalded skin syndrome (SSSS), or ecthyma.

In a 14^(th) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-12^(th) embodiments is Acute Bacterial Skin andSkin Structure Infection (ABSSSI), which most commonly include woundinfection, cellulitis/erysipelas, and major abscess.

ABSSSI accounts for nearly 10% of hospital admissions and 3.4-3.8million emergency department visits per year in the United States.Analyses of hospital discharge records indicate that 74% of ABSSSIadmissions involve empiric treatment with methicillin-resistantStaphylococcus aureus (MRSA) active antibiotics.

In a 15^(th) embodiment, the ABSSSI of the 14^(th) embodiment iscommunity-acquired ABSSSI.

In a 16^(th) embodiment, the community-acquired ABSSSI of the 15^(th)embodiment is caused by community-associated MRSA infection.

In a 17^(th) embodiment, the ABSSSI of any one of the 14^(th)-16^(th)embodiment is greater than or equal to 75 cm² in total surface area ofcontiguous involved tissue.

In an 18^(th) embodiment, the ABSSSI of any one of the 14^(th)-17^(th)embodiment comprises wound infection, cellulitis/erysipelas, and/ormajor abscess.

In a 19^(th) embodiment, the bacterial skin or skin structure infection(e.g., ABSSSI) of the 14^(th) embodiment is an infection prompting oroccurring during hospitalization.

In a 20^(th) embodiment, the ABSSSI of any one of the 1^(st)-19^(th)embodiments is moderate to severe ABSSSI.

In a 21^(st) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-20^(th) embodiments is a result of (or resultsfrom) skin injury, including but not limited to trauma, a surgicalprocedure, or IV drug use.

In a 22^(nd) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-20^(th) embodiments is a result of (or resultsfrom) vascular insufficiency or edema.

In a 23^(rd) embodiment, the human subject of any one of the1^(st)-22^(nd) embodiments is administered 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline orally under fasting condition.

For example, the human subject administered omadacycline has had nofood, antacids, or multivitamins containing multivalent cations (e.g.,aluminum, magnesium, calcium, bismuth, iron, or zinc), or drink, exceptwater, for at least 6 hours before each dosing; and, after each dosing,will take no food for 2 hours, no dairy products, antacids, ormultivitamins containing multivalent cations (e.g., aluminum, magnesium,calcium, bismuth, iron, or zinc) for 4 hours.

In a 24^(th) embodiment, the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline of any one of the 1^(st)-23^(rd) embodimentsis administered once per day (e.g., each oral dose is administered about24 hours apart). For example, the human subject may take the oral doseof omadacycline in the morning, after fasting overnight for at least 6hours.

In a 25^(th) embodiment, the subject of any one of the 1^(st)-24^(th)embodiments is treated up to and including about 14 days, up to andincluding about 13 days, up to and including about 12 days, up to andincluding about 11 days, up to and including about 10 days, up to andincluding about 9 days, up to and including about 8 days, or up to andincluding about 7 days, up to and including about 6 days, up to andincluding about 5 days, or up to and including about 4 days, such thatthe subject is treated.

In a 26^(th) embodiment, the subject of the 25^(th) embodiment istreated for 7-10 days.

In a 27^(th) embodiment, the subject of the 25^(th) embodiment istreated for 8 days.

In a 28^(th) embodiment, the salt of any one of the 1^(st)-27^(th)embodiments is a tosylate salt of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline/omadacycline.

In a 29^(th) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-28^(th) embodiments is known or suspected to becaused by Gram-positive pathogens.

In a 30^(th) embodiment, the Gram-positive pathogens of the 29^(th)embodiments may include (without limitation) Staphylococcus aureus,Staphylococcus lugdunensis, Streptococcus species, Streptococcusagalactiae, Streptococcus mitis, Enterococcus species (Enterococcusfaecalis (such as VRE or VSE), or Enterococcus faecium (such as VRE orVSE)), Streptococcus anginosus group (S. anginosus, S. constellatus, andS. intermedius, that is beta-, alpha- or non-hemolytic), Viridans groupStreptococci (VGS), Clostridium perfringens, Finegoldia magna, or acombination thereof.

In a 31^(st) embodiment, the Staphylococcus aureus of the 30^(th)embodiment is methicillin-resistant Staphylococcus aureus (MRSA), ormethicillin-susceptible Staphylococcus aureus (MSSA).

In a 32^(nd) embodiment, the Streptococcus species of the 30^(th)embodiment include Streptococcus anginosus group.

In a 33^(rd) embodiment, the Streptococcus species of the 30^(th)embodiment include beta-hemolytic Streptococci or S. anginosus.

In a 34^(th) embodiment, the Streptococcus species of the 30^(th)embodiment include non-hemolytic Streptococci or S. intermedius.

In a 35^(th) embodiment, the Streptococcus species of the 30^(th)embodiment include alpha-hemolytic Streptococci or S. constellatus.

In a 36^(th) embodiment, the Enterococcus species of the 30^(th)embodiment include Enterococcus faecalis (VSE).

In a 37^(th) embodiment, the Streptococcus species of the 30^(th)embodiment include Streptococcus pyogenes.

In a 38^(th) embodiment, the bacterial skin or skin structure infectionof any one of the 1^(st)-28^(th) embodiments is known or suspected to becaused by Gram-negative pathogens.

In a 39^(th) embodiment, the Gram-negative pathogens of the 38^(th)embodiment include Enterobacter cloacae, Escherichia coli, Klebsiellapneumoniae, Prevotella denticola, Prevotella melaninogenica, or acombination thereof.

In a 40^(th) embodiment, GI adverse events (AEs) associated withtreatment (if any), in any one of the 1^(st)-39^(th) embodiments, arepredominantly mild.

In a 41^(st) embodiment, GI adverse events (AEs) associated withtreatment (if any), in any one of the 1^(st)-40^(th) embodiments, do notresult in discontinuation of therapy.

In a 42^(nd) embodiment, the method of any one of the 1^(st)-41^(st)embodiments, has a greater clinical success rate than linezolid(N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide),where the linezolid is administered at 600 mg orally every 12 hours.

In a 43^(rd) embodiment, in any one of the 1^(st)-42^(nd) embodiments,successful Early Clinical Response (ECR) (e.g., 48 to 72 hours after thefirst dose), defined as survival with a greater than or equal to 20%reduction of lesion size compared to pre-treatment measurement (withoutreceiving any rescue antibacterial therapy), is achieved in the humansubject.

In a 44^(th) embodiment, in any one of the 1^(st)-43^(rd) embodiments,successful Clinical Response (CR) is achieved in the human subject aftertreatment completion, wherein successful Clinical Response is defined assurvival with resolution or improvement of one or more signs andsymptoms of infection to the extent that further antibacterial therapyis not necessary.

In a 45^(th) embodiment, in any one of the 1^(st)-44^(th) embodiments,AUC₀₋₂₄ after the first two doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is about 9,000 ng*h/mL,9,500 ng*h/mL, 10,000 ng*h/mL, or 10,500 ng*h/mL, or between any of thetwo above numbers.

In a 46^(th) embodiment, in any one of the 1^(st)-45^(th) embodiments,each dose of the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline orsalt thereof is administered as 150 mg tablets. That is, 3 tablets for450 mg oral dose, 2 tablets for 300 mg oral dose.

In a 47^(th) embodiment, the method of any one of the 1^(st)-46^(th)embodiments has a clinical success rate of about 70-100%.

In a 48^(th) embodiment, the clinical success rate of the 47^(th)embodiment is about 80-100%, about 79-98%, about 79-94%, about 84-98%,about 80-88%, or about 84-89%.

In a 49^(th) embodiment, the clinical success rate of the 47^(th) or the48^(th) embodiment is observed at 48-72 hours after the first oral dose,and is about 79-94%, or about 84-89%, or about 87.5%.

In a 50^(th) embodiment, the ABSSSI of the 49^(th) embodiment consistsessentially of wound infection, and the clinical success rate is about84-94%, or about 89%.

In a 51^(st) embodiment, the ABSSSI of the 49^(th) embodiment consistsessentially of cellulitis/erysipelas, and the clinical success rate isabout 74-84%, or about 79%.

In a 52^(nd) embodiment, the ABSSSI of the 49^(th) embodiment consistsessentially of major abscess, and the clinical success rate is about90-98%, or about 94%.

In a 53^(rd) embodiment, the clinical success rate of the 47^(th) or the48^(th) embodiment is overall clinical success rate observed at about7-14 days after the last dose of treatment, and is about 79-98%, about75-95%, about 79-89%, 84%, about 95-100%, or about 98%.

In a 54^(th) embodiment, the ABSSSI of the 53^(rd) embodiment consistsessentially of wound infection, and the overall clinical success rate isabout 80-85%, or is about 82-83%.

In a 55^(th) embodiment, the ABSSSI of the 53^(rd) embodiment consistsessentially of cellulitis/erysipelas, and the overall clinical successrate is about 85-91%, about 87-88%, or is about 88%.

In a 56^(th) embodiment, the ABSSSI of the 53^(rd) embodiment consistsessentially of major abscess, and the overall clinical success rate isabout 80-88%, or about 84%.

In a 57^(th) embodiment, in any one of the 1^(st)-56^(th) embodiments,the 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereofhas an efficacy greater than linezolid for the treatment of thebacterial skin or skin structure infection (e.g., ABSSSI). Linezolid isN-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide,marked under the trademark ZYVOX™. In certain embodiments, linezolid isadministered at 600 mg orally or 600 mg intravenously every 12 hrs.

In a 58^(th) embodiment, in any one of the 1^(st)-57^(th) embodiments,the 9-[(2,2-dimethyl-propyl amino)-methyl-]-minocycline or salt thereofis administered with a pharmaceutically acceptable carrier.

In a 59^(th) embodiment, the pharmaceutically acceptable carrier of the58^(th) embodiment is acceptable for oral administration.

In a 60^(th) embodiment, in any one of the 1^(st)-59^(th) embodiments,the method has a clinical success rate, e.g., that based on a reductionof lesion size at 48-72 hours after the first dose of about 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% or greater.

In a 61^(st) embodiment, in any one of the 1^(st)-60^(th) embodiments,the method has a clinical success rate, e.g., clinical success based oninvestigator's assessment of clinical response at 7-14 days (e.g., 7-10days, or 7, 8, 9, 10 days) after the last dose of about 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or greater.

In a 62^(nd) embodiment, in any one of the 1^(st)-61^(st) embodiments,the human subject has concurrent bacteremia.

In a 63^(rd) embodiment, in any one of the 1^(st)-62^(nd) embodiments,the human subject is obese (e.g., those with BMI≥30).

In a 64^(th) embodiment, in any one of the 1^(st)-63^(rd) embodiments,the human subject has mild-to-moderate renal impairment.

In a 65^(th) embodiment, in any one of the 1^(st)-64^(th) embodiments,the human subject has hepatic impairment.

In a 66^(th) embodiment, in any one of the 1^(st)-65^(th) embodiments,the human subject is over 45 yrs old, over 50 yrs old, over 55 yrs old,over 60 yrs old, over 65 yrs old, over 70 yrs old, or over 75 yrs old.

In a 67^(th) embodiment, in any one of the 1^(st)-66^(th) embodiments,the human subject is an IV drug user.

Further details of the various embodiments are described below.

2. Definitions

“ABSSSI” or “Acute Bacterial Skin and Skin Structure Infection,” is alsosometimes referred to skin and soft tissue infection (SSTI). It is atype of infection of skin and associated soft tissues, such as looseconnective tissue and mucous membranes. The FDA of the U.S. Departmentof Health and Human Services published in October 2013 a documententitled “Guidance for Industry Acute Bacterial Skin and Skin StructureInfections: Developing Drugs for Treatment” (“the Guidance,”incorporated herein by reference), to assist sponsors in the clinicaldevelopment of drugs for the treatment of ABSSSI. The Guidance definesABSSSI as cellulitis/erysipelas, wound infection, and major cutaneousabscess with a measured surface area of greater than or equal to 75 cm².The Guidance does not address less serious skin infections, such asimpetigo, and minor cutaneous abscess, as well as infections needingmore complex treatment regimens, such as infections resulting fromanimal or human bites, necrotizing fasciitis, diabetic foot infection,decubitus ulcer infection, myonecrosis, and ecthyma gangrenosum orinfections less than 75 cm² that may require antibiotic treatment.

Thus in certain embodiments, ABSSSI as used herein includescellulitis/erysipelas, wound infection, and major cutaneous abscess. Incertain embodiments, the cellulitis/erysipelas, wound infection, and/ormajor cutaneous abscess has a minimum lesion surface area ofapproximately 75 cm². The lesion size can be measured by the area ofredness, edema, or induration.

In certain embodiments, for areas of ABSSSI that involve certain bodysurface sites, such as the face, or for young children appropriate andeligible for a phase 3 clinical trial, ABSSSI may include lesions with asurface area smaller than 75 cm², such as about 70 cm², 65 cm², 60 cm²,55 cm², 50 cm², 45 cm², or about 40 cm².

In certain embodiments, ABSSSI may involve certain body locations, suchas on the face, near the eye, or on the hand, where lesions may besmaller than even 40 cm² but may still be treated with antibiotic.

In certain other embodiments, ABSSSI does not include lesions with asurface area smaller than 75 cm².

The size of the treatable skin and skin structure infection can bemeasured by the total surface area of contiguous involved tissue.Methods to assess lesion size generally include, but are not limited to,the following: (1) manual measurement of length multiplied byperpendicular width; (2) digital planimetry; and (3) computer-assistedtracings. For example, the total surface area of contiguous involvedtissue can be calculated as the product of the maximum length(head-to-toe) multiplied by the maximum width (measured perpendicular tolength) as measured by using, e.g., a wound ruler.

In certain embodiments, ABSSSI as used herein includescellulitis/erysipelas, wound infection, major cutaneous abscess, as wellas less serious skin infections, such as impetigo, and minor cutaneousabscess (e.g., those with lesion surface area of less than 75 cm²). Inother embodiment, ABSSSI does not include less serious skin infections,such as impetigo, and minor cutaneous abscess.

“Involved tissue” is defined as tissue exhibiting evidence of one ormore of the following: erythema, edema or induration.

“Wound infection” includes an infection characterized by purulentdrainage from a wound with surrounding erythema, edema, and/orinduration. In certain embodiments, the surrounding erythema, edema,and/or induration extends at least 5 cm in the shortest distance fromthe peripheral margin of the wound.

“Cellulitis/erysipelas” includes a diffuse skin infection characterizedby spreading areas of erythema, edema, and/or induration.

“Major abscess” includes an infection characterized by a collection ofpus within the dermis or deeper with surrounding erythema, edema, and/orinduration. In certain embodiments, the surrounding erythema, edema,and/or induration extends at least 5 cm in the shortest distance fromthe peripheral margin of the abscess.

Common bacterial pathogens causing ABSSSI include but are not limitedto: Streptococcus pyogenes and Staphylococcus aureus includingmethicillin-resistant S. aureus, as well as the less common causesinclude other Streptococcus species, Enterococcus faecalis, orGram-negative bacteria.

In certain embodiments, the ABSSSI is community acquired ABSSSI, which(as opposed to hospital-acquired ABSSSI) is contracted by a person withno or little contact with the healthcare system. In contrast,hospital-acquired ABSSSI is contracted by one who lives in long-termcare facilities or have recently visited a hospital or other healthcarefacility.

“Adverse Event (AE)” includes any untoward, undesired, or unplannedevent in the form of signs, symptoms, disease, or laboratory orphysiologic observations occurring in a person given a dose or a seriesof doses of the subject 9-aminomethyl minocycline compound(9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline) during treatment.

The term “effective amount” here includes the amount of omadacyclineneeded to treat a bacterial infection. For example, an effective amountdescribes an efficacious level sufficient to achieve the desiredtherapeutic effect through the killing of bacteria and/or inhibition ofbacterial growth. Preferably, the bacterial infection is treated whenthe pathogen (e.g., bacteria) is eradicated.

“Fasting condition,” as used herein, includes giving the subject to betreated no food, antacids, or multivitamins containing multivalentcations (e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc), ordrink, except water, for at least 6 hours before each dosing; and, aftereach dosing, no food for 2 hours, no dairy products, antacids, ormultivitamins containing multivalent cations (e.g., aluminum, magnesium,calcium, bismuth, iron, or zinc) for 4 hours.

“Furuncles/boils” includes deep bacterial infection of hair follicles.

“Carbuncle” includes coalescence of multiple furuncles.

“Staphylococcal scalded skin syndrome (SSSS)” includes red blisteringskin caused by exotoxins from toxigenic strains of the bacteriaStaphylococcus aureus.

“Ecthyma” includes crusted erosions or ulcerations (a deep form ofimpetigo) caused by Streptococcus pyogenes and/or Staphylococcus aureus.

“Clinical Response” for ABSSSI can be based on the percent reduction inthe lesion size at 48 to 72 hours compared to baseline, measured inpatients who did not receive rescue therapy and are alive. A clinicalresponse in a patient in this timeframe generally is defined as apercent reduction in lesion size greater than or equal to 20 percentcompared to baseline.

Evidence of a systemic inflammatory response may be indicated by atleast one of the following: elevated white blood cell (WBC) count (e.g.,greater than or equal to 10,000 cells/mm³) or leukopenia (e.g., lessthan or equal to 4,000 cells/mm³); elevated immature neutrophils (e.g.,greater than or equal to 15% band forms) regardless of total peripheralwhite blood cell (WBC) count; lymphatic involvement, e.g., lymphangitisor lymphadenopathy that is proximal to and in a location that suggestsdrainage from the qualifying infection; fever or hypothermia documentedby a temperature of greater than about 38.0° C. [100.4° F.] or less than36.0° C. [95.5° F.].

The term “treating” or “treatment” refers to the amelioration,eradication, or diminishment of one or more symptoms of the disorder,e.g., a bacterial skin or skin structure infection (e.g., ABSSSI), to betreated. In certain embodiments, the disorder term includes theeradication of bacteria associated with the infection to be treated.

The term “prophylaxis” means to prevent or reduce the risk of bacterialinfection.

The term “resistance” or “resistant” refers to the antibiotic/organismstandards as defined by the Clinical and Laboratories StandardsInstitute (CLSI) and/or the Food and Drug Administration (FDA).

“Pharmaceutically acceptable carrier” includes substances capable ofbeing co-administered with the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or salt thereof, and which allow the drugcompound to perform its intended function, e.g., treat or prevent abacterial skin or skin structure infection. Suitable pharmaceuticallyacceptable carriers include but are not limited to water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds of the invention.

In certain embodiments, the pharmaceutically acceptable (inert) carriersare in the form of tablets, capsules, lozenges, troches, hard candies,powders, sprays, creams, salves, suppositories, jellies, gels, pastes,lotions, ointments, aqueous suspensions, injectable solutions, elixirs,syrups, and the like. Such carriers include solid diluents or fillers,sterile aqueous media and various non-toxic organic solvents, etc.Moreover, oral pharmaceutical compositions can be suitably sweetenedand/or flavored. In general, the therapeutically-effective omadacyclineof this invention are present in such dosage forms at concentrationlevels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

In certain embodiments, the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or salt thereof is formulated as a tabletwith excipients including lactose monohydrate, microcrystallinecellulose, sodium stearyl fumarate, crospovidone, colloidal siliconedioxide, sodium bisulfite, polyvinyl alcohol, titanium dioxide, talc,glycerol monocaprylocaprate, sodium lauryl sulfate, and/or iron oxideyellow.

In addition to treatment of human subjects, the therapeutic methods ofthe invention also will have significant veterinary applications, e.g.for treatment of livestock such as cattle, sheep, goats, cows, swine andthe like; poultry such as chickens, ducks, geese, turkeys and the like;horses; and pets such as dogs and cats. Also, omadacycline and saltsthereof may be used to treat non-animal subjects, such as plants.

With the invention generally described above, the examples below furtherillustrates (but not limit) the invention described herein.

EXAMPLES Example 1 Effect of Food on the Bioavailability of Omadacyclinein Healthy Volunteers

Omadacycline (OMC, 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline)is a first-in-class aminomethylcycline antibiotic that is characterizedby improved in vitro antimicrobial activity (Honeyman et al, AntimicrobAgents Chemother. 59:7044-7053, 2015). It demonstrates in vitro activityagainst a broad range of Gram-positive and Gram-negative aerobes, manyanaerobes, and atypical pathogens including Legionella spp. andMycoplasma spp. (Macon et al, Antimicrob Agents Chemother. 58:1127-1135,2014; Dubois et al, In vitro activity of omadacycline against Legionellapneumophila. Abstract presented at the 55^(th) ICAAC, San Diego, Calif.,Sep. 17-21, 2015; Kim et al, Activity and efficacy of omadacyclineagainst Clostridium difficile. Abstract presented at the 2016 ECCMID,Amsterdam, the Netherlands). In patients with complicated skin and skinstructure infection, omadacycline demonstrated clinical efficacy andtolerability that was comparable to linezolid (Noel. et al, AntimicrobAgents Chemother. 56:5650-5654, 2012; Noel et al, Safety and efficacy ofPTK 0796 (omadacycline) as treatment of complicated skin and soft tissueinfection (cSSTI). Poster presented at 23^(rd) European Congress onClinical Microbiology and Infectious Diseases, March 31-Apr. 3, 2012,London, UK).

Phase 3 studies have concluded with omadacycline as oral and intravenous(IV) monotherapy in patients with acute bacterial skin and skinstructure infection (ABSSSI).

During the development process, oral omadacycline formulations haveevolved from free-base in a capsule through a series of tablet and saltformulations in order to optimize oral bioavailability while improvingtolerability. The current phase 3 tablet formulation is the tosylatesalt of omadacycline, which has been shown to have an absolutebioavailability of 34.5% when administered under fasting conditions. Theprimary objective of this study was to evaluate the relativebioavailability of a single oral 300 mg dose of omadacycline(administered as the phase 3 tablet formulation) at various times afterthe consumption of food in healthy adult subjects.

The result of this study showed that food consumption has an effect onthe oral bioavailability of a single 300 mg OMC dose.

Briefly, the study was a phase 1, randomized, open-label 4-period,crossover study. Before dosing on Day 1 of Period 1, subjects wererandomized to one of four treatment sequences (see Table 1). On Day 1 ofeach period, subjects received a single oral dose of 300 mg omadacycline(2×150 mg tablets) at various times after the consumption of food. Therewas a washout period of at least 5 days between each dosing period. Afinal study completion visit occurred 6 to 10 days after the last doseof omadacycline.

TABLE 1 Treatment Sequences Sequence Period 1 Period 2 Period 3 Period 4ADBC A D B C BACD B A C D CBDA C B D A DCAB D C A B A subjects fastedovernight (no food or drink except for water for at least 6 hours beforedosing); a standard high-fat (nondairy) meal was served 3 hours afterdosing B a standard high-fat (nondairy) meal completed at 4 hours beforedosing C a standard high-fat (nondairy) meal completed at 2 hours beforedosing D a standard high-fat meal including dairy completed at 2 hoursbefore dosing

The high-fat (approximately 50% of total caloric content of the meal)and high-calorie (approximately 800 to 1000 calories) meal followed Foodand Drug Administration guidance recommendations, and providedapproximately 150, 250, and 500 to 600 calories from protein,carbohydrate, and fat, respectively (FDA Guidance, 2002). These mealswere to be consumed within 20 minutes. Dose administration forTreatments B, C, and D was based off of the end time of the meal. Duringall 4 treatment periods, subjects received no food or drink except waterfor at least 3 hours after dosing and no dairy products, antacids ormultivitamins for 4 hours after dosing.

A total of 32 subjects were enrolled and dosed in at least one treatmentperiod. Overall mean age was 32.3 years, with a range of 21 to 50 years;47% were male (Table 2). One subject was discontinued from the studybecause of a positive alcohol screen at baseline of period 3 and did notreceive Treatments A and D. One subject requested withdrawal and did notreceive Treatments B and C. PK data were available for 31 subjects foreach treatment condition.

TABLE 2 Baseline Demographics Subjects (n = 32) Age, years^(a) 32.2(8.0) Age range, years 21-50 Male, n (%) 15 (46.9) Race, n (%) white 24(75) black/African American 8 (25) Hispanic/Latino 12 (37.5) Height,cm^(a) 168.0 (9.5) Weight, kg^(a) 71.5 (13.4) BMI (body Mass Index),kg/m^(2 a) 25.2 (3.2) ^(a) Mean (Standard Deviation)

Blood samples for pharmacokinetic (PK) assessments of omadacycline werecollected before dosing (predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6,8, 12, 16, and 24 hours after dosing in each period. PK parametersincluded: Area under the plasma concentration-time curve (AUC) from time0 to 24 hours after dosing (AUC₀₋₂₄); AUC from time 0 to the lastquantifiable concentration (AUC₀-t); AUC time 0 extrapolated to infinity(AUC_(0-inf)); Maximum (peak) observed plasma concentration (C_(max));Time to reach C_(max) (T_(max)); Terminal elimination half-life(T_(1/2)); Terminal phase rate constant (λ_(Z)).

Safety and tolerability was assessed by: Adverse events (AEs); vitalsign measurements at multiple time-points within 24 hours post-dose ineach treatment period; and clinical laboratory tests 24 hours post-dosein each treatment period.

For statistical analysis, individual PK parameters for omadacycline weresummarized with descriptive statistics. Geometric means were determinedfor AUC and C_(max). PK parameters were evaluated usingnon-compartmental analysis using Phoenix® WinNonlin® (Pharsight Corp,St. Louis, Mo.), Version 6.2.1. Confidence intervals (CI) for testtreatments (fed states: Treatments B, C, and D) compared with thereference treatment (fasted state: Treatment A) were constructed forAUC₀₋₂₄, AUC_(0-t), AUC_(0-inf), and C_(max). Absence of the effect offood was concluded if the 90% CI for the test-to-reference ratios (B/A,C/A, or D/A) of geometric means were contained within the criterioninterval of 80% to 125% for AUC₀₋₂₄, AUC_(0-t), AUC_(0-inf), andC_(max). For T_(max), the Wilcoxon signed rank test was performed.p≤0.05 was considered statistically significant.

A linear mixed-effect model with treatment condition, sequence, andperiod as fixed effects and subject nested within sequence as a randomeffect was fitted to the natural log-transformed PK parameters forestimation of effects and 90% confidence intervals (CIs) for the fedstates compared with the fasted state.

TABLE 3 Plasma PK Parameters for Omadacycline after a Single 300 mg OralDose Mean (Coefficient of Variation) Treatment A Treatment B Treatment CTreatment D Parameter N = 31 N = 31 N = 31 N = 31 AUC_(0-24’) mcg*h/mL7.2 (28.1) 6.1 (26.3) 4.2 (23.4) 2.8 (44.3) AUC_(0-t’) mcg*h/mL 7.2(28.1) 6.1 (26.3) 4.2 (23.4) 2.8 (44.4) AUC_(0-inf’) mcg*h/mL 10.2(27.0)^(b) 8.8 (29.2) 6.0 (25.4) 4.0 (44.1) C_(max’) mcg/mL 0.6 (25.3)0.6 (25.0) 0.4 (22.4) 0.3 (42.6) T_(max’) h^(a) 2.5 (1.5, 4.1) 2.9 (1.0,6.0) 2.9 (1.0, 6.0) 2.9 (1.0, 6.0) T_(1/2’) h 13.8 (10.3)^(b) 13.6(12.7) 13.6 (12.2) 13.5 (14.7)

PK analysis showed that, for the 31 subjects included in the PKanalysis, fasted AUC_(0-inf), AUC_(0-t), and AUC₀₋₂₄ were 10.2, 7.2, and7.2 mcg*h/mL, respectively, and C_(max) was 0.6 mcg/mL. Across alltreatment periods, mean T₁₁₂ ranged from 13.5 to 13.8 hours, and medianT_(max) ranged from 2.5 to 2.9 hours. No treatment-related adverseevents or clinically relevant changes in laboratory values, or vitalsigns occurred. See Table 3.

A significant reduction in systemic exposure to omadacycline wasobserved for all three treatments (Treatments B, C, and D) vs. TreatmentA (FIG. 1 and Table 4).

TABLE 4 Statistical Analysis of the Effect of Food on PlasmaPharmacokinetic Parameters of Omadacycline (N = 31) Ratio of 90%Geometric CI of Geometric Treatment LS Ratio Parameter Treatment LS MeanComparison Mean (%) (%) AUC_(0-24’) A 7.4 mcg*h/L B 6.2 B/A 83.4 74.9,92.7 C 4.3 C/A 57.7 51.9, 64.2 D 2.8 D/A 37.3 33.6, 41.5 AUC_(0-t’) A7.4 mcg*h/L B 6.2 B/A 83.3 74.9, 92.7 C 4.3 C/A 57.7 51.9, 64.1 D 2.8D/A 37.3 33.5, 41.4 AUC_(0-inf’) A* 10.6 mcg*h/L B 9.0 B/A 84.7 75.8,94.6 C 6.2 C/A 58.4 52.3, 65.3 D 4.0 D/A 37.9 34.0, 42.3 C_(max’) A 0.66mcg/L B 0.56 B/A 84.5 75.9, 94.1 C 0.39 C/A 60.1 54.0, 66.9 D 0.27 D/A40.7 36.5, 45.2 *N = 30, a terminal mono-exponential phase could not beidentified for one subject. CI, confidence interval; LS, least squares

The effect of food was more pronounced when a high-fat meal was consumedcloser to dosing and when dairy was included in the meal. Compared witha fasted dose, omadacycline exposure (C_(max) and AUC) was Reduced by15% to 17% for a nondairy meal 4 hours before dosing; reduced by 40% to42% for a nondairy meal 2 hours before dosing; and reduced by 59% to 63%for a dairy meal 2 hours before dosing. The between-subject variabilityin systemic exposure to omadacycline was similar for Treatments A, B andC (CV 22.4-29.2%) for C_(max) and AUC. By contrast, for Treatment D theCV was 42.6-44.4% for these parameters.

Concerning safety and tolerability, two subjects experienced treatmentemergent AEs (one reported nausea, one reported somnolence); both eventswere of mild intensity and considered unrelated to study drug. Nosubject discontinued the study for an AE, and no subject experienced aserious AE (SAE). A slight increase from baseline in heart rate (median8 to 10 bpm at 4 to 6 hours post dose) was observed for Treatment A(i.e., the group with highest omadacycline exposure). In all othertreatment groups, the median change from baseline in heart rate was ≤3bpm at all measured time points. No notable changes in blood pressurewere observed. There were no clinically significant changes in clinicallaboratory tests.

The results showed that a single oral dose of omadacycline was welltolerated. Administration of a 300 mg dose within 2 to 4 hours of foodreduced the bioavailability compared with the fasted state. Thuspreferably, once daily oral omadacycline should be administered at least6 hours following a meal.

Example 2 A Phase I, Randomized, Double-Blind, 3-Period, Crossover Studyto Evaluate Safety, Tolerability, and Pharmacokinetics of Multiple OralDoses of Omadacycline or Placebo in Healthy Adult Subjects

The primary objective of this study was to assess and compare thepharmacokinetics (PK) of 300-, 450-, and 600-mg doses of oralomadacycline administered daily over 5 days. The secondary objective ofthe study was to evaluate the safety and tolerability of multiple dosesof omadacycline in healthy adult subjects.

For the treatment of ABSSSI, the then anticipated therapeutic daily oraldose (excluding any loading dose) was 300 mg. For potential futurestudies, or for administration of a loading dose using the oralformulation, it is possible that a daily dose higher than 300 mg couldbe used to achieve omadacycline concentrations sufficient to treattarget bacteria in the organs/tissues of interest. One early clinicalstudy evaluated single oral doses of omadacycline up to 600 mg, but nostudies have evaluated multiple daily doses higher than 300 mg. Thisstudy was designed to obtain data on the safety, tolerability, andpharmacokinetics (dose linearity and proportionality) of multiple oraldoses of omadacycline at daily doses higher than 300 mg. Placebo groupswere included as a reference to minimize potential bias in assessingtolerability.

Multiple daily oral doses of 300, 450, and 600 mg omadacycline orplacebo were chosen to be administered in this study. The lowest dose of300 mg had been evaluated in multiple dose studies and had been welltolerated; this daily dose has also been studied in Phase 3 studies inABSSSI. Single oral doses up to 600 mg were administered in capsules tohealthy adult subjects in 1 early clinical study and were determined tohave an acceptable safety profile. There was some increased incidence ofGI AEs at oral doses of 400 mg or greater, though events were typicallymild (none were severe), and it is possible that some of these eventsmay have been related to the oral formulation. Multiple daily doses ofup to 600 mg using the final optimized tablet formulation ofomadacycline were expected to have acceptable safety profiles, but thiswas important to assess in a small carefully controlled Phase 1 studybefore evaluating these doses in larger clinical studies.

Thus the study was designed as a Phase 1, randomized, double-blind,3-period, crossover study in healthy adult subjects. The study consistedof a screening period (Day −21 through Day −2), 3 baseline periods (Day−1 of each period), 3 treatment periods (Day 1 through Day 6 of eachperiod), and a study completion visit (within 6 to 10 days after thelast dose of study drug in Period 3). There was a washout of at least 5days between the last dose in one period and the first dose in the nextperiod. Subjects were confined to the study site from Day −1 of Period 1until discharge on Day 6 of Period 3, after the 24-hour blood sampling,urine sampling, and safety assessments were completed. Subjects returnedto the study center 6 to 10 days after the last dose of study drug inPeriod 3 for the study completion visit.

Subject Selection

Healthy, non-smoking, male and female subjects were eligible forparticipation in the study if they were between 18 and 55 years of age(inclusive), weighed ≥50 kg, had a body mass index between 18 and 30kg/m2 (inclusive), met all eligibility criteria during screening(performed within 21 days before dosing in Period 1) and at baseline(Day −1) for Period 1, and provided written informed consent. Healthstatus was determined by past medical history, clinical laboratorytests, vital signs (oral body temperature, systolic blood pressure,diastolic blood pressure, and heart rate), 12-lead electrocardiogram(ECG), and physical examination at screening. Eligibility criteriaincluded ability to swallow up to 4 tablets in succession.

Subjects were excluded from participation in the study for priortreatment with omadacycline, recent use of other investigational drugs;ECG abnormalities; inability to tolerate oral medications; pregnancy orbreastfeeding; use of tobacco products, prescription drugs, herbalsupplements, or over-the-counter medications or intake of xanthine(e.g., caffeine)—containing food or beverages within a specified timeframe before study initiation; blood loss/donation; low hemoglobinlevels; high creatinine or blood urea nitrogen levels; urinaryobstruction/difficulty voiding; positive alcohol or drug test;hypersensitivity or allergy to any tetracycline; signs of liver diseaseor liver injury; significant illness within 2 weeks of study initiation;any planned medical intervention that might interfere with the study; ora history of diseases or medical conditions as specified in the studyprotocol.

Study Design

On Day 1 through Day 5 of each period, subjects received once-daily,after a fast of 6 hours, one of the following treatments (omadacyclineor placebo) according to the randomization schedule:

A. 300 mg omadacycline (2×150-mg tablets)

AP. Placebo for 300 mg omadacycline (2×placebo tablets)

B. 450 mg omadacycline (3×150-mg tablets)

BP. Placebo for 450 mg omadacycline (3×placebo tablets)

C. 600 mg omadacycline (4×150-mg tablets)

CP. Placebo for 600 mg omadacycline (4×placebo tablets)

All doses of study drug were administered in the morning with no food ordrink except for water at least 6 hours prior to dosing. Subjects thenhad no food or drink except water for at least 2 hours after dosing andno dairy products, antacids, or multivitamins for 4 hours after dosing.

Before the dosing, subjects underwent screening evaluations to determineeligibility within 21 days before dosing in Period 1. Subjects were thenadmitted to the clinical site on the day before dosing (Day −1 ofPeriod 1) for baseline evaluations. Before dosing on Day 1 of Period 1,up to 30 subjects (24 omadacycline, 6 placebo) were randomly assigned to1 of 3 treatment sequences using a Latin Square design as presented inthe following table:

Sub- Number of Period Period Period Sequence sequence Subjects 1 2 3 11A 8 omadacycline A C B 1B 2 placebo AP CP BP 2 2A 8 omadacycline B A C2B 2 placebo BP AP CP 3 3A 8 omadacycline C B A 3B 2 placebo CP BP AP

About ten subjects were randomly assigned to each sequence. Placebo wasadministered to 2 subjects in each sequence as a reference to assesstolerability. Subjects assigned to omadacycline received omadacyclineduring all 3 periods and at all tested dose levels. Subjects assigned toplacebo received placebo during all 3 periods. Investigators andsubjects were blinded to whether the subject was receiving omadacyclineor placebo.

Study Assessment

1. Plasma Pharmacokinetics

Serial blood samples for pharmacokinetic (PK) analysis of omadacyclinewere collected at specified time points through 24 hours after dosing onDay 1 and Day 5 of each period. Specifically, blood samples for PKassessments of omadacycline were collected from all subjects at thefollowing time points: before dosing (predose) and at 0.5, 1, 1.5, 2,2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing on Day 1 and Day 5 ineach period. The 24-hour blood sample for Day 1 was collected prior todosing on Day 2 for each period.

Non-compartmental PK parameters were determined on Days 1 and 5 of eachperiod from plasma omadacycline concentration and actual time data usingPhoenix® WinNonlin® (Certara, Princeton, N.J.) Version 6.2.1., includingarea under the plasma concentration versus time curve (AUC) from time 0to 24 hours after dosing (AUC₀₋₂₄), AUC from time 0 to the lastquantifiable concentration (AUC_(last)), maximum observed plasmaconcentration (C_(max)), time to reach maximum observed plasmaconcentration (T_(max)), terminal elimination half-life (T₁₁₂), terminalphase rate constant (λ_(z)) and the accumulation factor (Rac) of AUC₀₋₂₄and C_(max).

Subjects that received omadacycline and had at least one evaluable PKparameter were included in the PK analysis population; however, subjectsmay have been excluded from the PK population if they missed doses, haddiarrhea, or had vomiting at or before a time equal to twice the medianT_(max).

2. Urine Pharmacokinetics

Urine samples were collected from a subset of subjects at specifiedintervals on Day 5 of Period 2 and on Day 1 and Day 5 of Period:predose, 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after dosing. The12 to 24-hour interval urine sample for Day 1 was collected prior todosing on Day 2. Urine samples were only collected from a subset ofsubjects because analysis of urine PK was added by an amendment to thestudy protocol after the study was already underway.

The following urine PK parameters were determined from urineomadacycline concentration and collection interval data using SASVersion 9.2: renal clearance (CLr), fraction of the dose excretedunchanged in urine from 0 to 24 hours after dosing (Fe₀₋₂₄), and amountof drug excreted unchanged in urine over 24 hours after dosing(Ae_(t1-t2)). Additional parameters Ae₀₋₄, Ae₄₋₈, Ae₈₋₁₂, Ae₁₂₋₂₄, andAe₀₋₂₄ were also calculated.

3. Safety and Tolerability

Safety assessments include monitoring of adverse events (AEs), clinicallaboratory test results, vital sign measurements, 12-leadelectrocardiogram (ECG) results, and physical examination findings. Allrandomly assigned subjects who received at least one dose of any studydrug (omadacycline or placebo) were included in the safety analysispopulation. Adverse events were coded by preferred term and system organclass using MedDRA Version 17.1.

Safety and tolerability were assessed by the monitoring and recording ofAEs, clinical laboratory test results (hematology, serum chemistry, andurinalysis), vital sign measurements (oral body temperature, systolicblood pressure, diastolic blood pressure, and HR), 12-lead ECG results,and physical examination findings.

Statistical Analysis for Pharmacokinetic Study:

Individual plasma and urine concentration and time deviation data werepresented in data listings. Plasma and urine concentration data weresummarized by day and time point or interval for each treatment usingdescriptive statistics (number of subjects, mean, SD, coefficient ofvariation [CV], median, minimum, and maximum). Concentrations that werebelow the limit of quantification (BLQ) were treated as zero in theplasma and urine concentration descriptive statistics summaries. Meanand individual plasma concentration versus time profiles were presentedin figures on both linear and semilogarithmic scales.

Non-compartmental PK parameters were determined from plasmaconcentration and actual time data using Phoenix® WinNonlin® (Certara,Princeton, N.J.) Version 6.2.1 or higher. Urine PK parameters weredetermined from urine concentration and collection interval data usingSAS Version 9.2 or higher. All further statistical analyses wereperformed using SAS® software (SAS Institute, Cary, N.C.), Version 9.2.

For the PK analysis, BLQ values were treated as zero with the exceptionthat a BLQ value between 2 quantifiable concentrations were set asmissing. Missing concentrations were treated as missing from the PKparameter calculations. If consecutive BLQ concentrations were followedby quantifiable concentrations in the terminal phase, thoseconcentrations after BLQ concentrations were treated as missing.

The individual PK parameters were presented in data listings.Descriptive statistics (number of subjects, mean, SD, CV, median,minimum, and maximum) were calculated for the PK parameter estimatesafter dosing on Day 1 and Day 5 of each period (e.g., AUC₀₋₂₄,AUC_(last), C_(max), T_(max), T₁₁₂, and Rac [Day 5 only] from plasmaconcentrations; CLr, Fe₀₋₂₄, and Ae₀₋₂₄ from urine concentrations).Geometric means were included for AUC₀₋₂₄, AUC_(last), and C_(max).

A linear mixed-effect model (SAS PROC MIXED) with treatment (A, B, andC), sequence (1A, 2A, and 3A), and treatment period as fixed effects andsubject nested within sequence as a random effect were fitted to thenatural log-transformed dose normalized PK parameters AUC₀₋₂₄/Dose,AUC_(last)/Dose, and C_(max)/Dose after dosing on Day 1 and Day 5 ofeach period for use in estimation of effects and construction ofconfidence intervals (CIs). Point estimates and 90% CIs for differenceson the log scale were exponentiated to obtain estimates for the ratiosof geometric means and respective 90% CIs on the original scale. Noadjustment was made for multiplicity.

Dose linearity across all 3 dose levels was assessed by fittingomadacycline C_(max), AUC_(last), and AUC₀₋₂₄ after both the Day 1 andDay 5 doses to a power model (10): ln(PK)=a+b×ln(Dose)+error, where PKwas the PK parameter, a was the intercept and b was the slope. Theestimates of slope b were reported along with the corresponding 2-sided90% CIs.

For statistical analysis of accumulation of omadacycline, a linearmixed-effect model with day as a fixed effect and subject as randomeffect was fitted to the natural log-transformed C_(max) and AUC₀₋₂₄ toconstruct 90% CIs for Day 5 compared with Day 1 (at each dose levelseparately).

Results

a. Demographics, Baseline Characteristics, and Disposition of StudySubjects

Of the 33 subjects enrolled in the study, 26 were assigned to receiveomadacycline and 7 were assigned to receive placebo. Demographic andbaseline characteristics were generally similar between omadacycline andplacebo treatment groups (Table 2-1) and across all omadacyclinetreatment sequences (data not shown). The majority of subjects in thestudy were white (57.6%) and male (81.8%). The overall mean age ofsubjects was 36.9 years, with a range of 21 to 55 years.

TABLE 2-1 Demographics and Baseline Characteristics of Subjects in theStudy^(a) Omadacycline Placebo Overall (N = 26) (N = 7) (N = 33) Age,years Mean (SD) 35.6 (±10.4) 41.9 (±11.6) 36.9 (±10.8) Min, max 21, 5525, 53 21, 55 Sex, n (%) Male 21 (80.8) 6 (85.7) 27 (81.8) Female 5(19.2) 1 (14.3) 6 (18.2) Race, n (%) White 15 (57.7) 4 (57.1) 19 (57.6)Black or 9 (34.6) 3 (42.9) 12 (36.4) African American Asian 2 (7.7) 0 2(6.1) Ethnicity, n (%) Hispanic or 10 (38.5) 3 (42.9) 13 (39.4) LatinoNot Hispanic 16 (61.5) 4 (57.1) 20 (60.6) or Latino Height, cm Mean (SD)173.12 (±9.17) 172.89 (±4.31) 173.07 (±8.32) Min, max 155.2, 192.4165.6, 177.4 155.2, 192.4 Weight, kg Mean (SD) 78.67 (±10.33) 83.77(±4.80) 79.75 (±9.60) Min, max 62.7, 101.4 76.7, 90.4 62.7, 101.4 Bodymass index, kg/m² Mean (SD) 26.25 (±2.72) 28.04 (±1.45) 26.63 (±2.59)Min, max 19.4, 29.8 25.8, 29.9 19.4, 29.9

All 33 subjects received at least one dose of study drug (omadacyclineor placebo) and were included in the safety analysis population.Twenty-five of the 26 omadacycline-treated subjects (96.2%) wereincluded in the PK analysis population (one subject was excluded fromthis population due to vomiting after dosing). Four omadacycline-treatedsubjects (15.4%) and one placebo-treated subject (14.3%) discontinuedthe study; these early discontinuations were due to treatment-emergentadverse events (TEAEs) in 4 subjects (see below); in addition oneomadacycline-treated subject was lost to follow-up. Thus, 22 subjectsreceived all 5 doses of 300-, 450-, and 600-mg omadacycline and 6subjects received all 5 doses of placebo in Periods 1, 2, and 3. Thesesubjects were considered to have completed the study.

b. Plasma Pharmacokinetics

The preliminary results of the PK study at the end of Day 1 and Day 5were summarized below.

Doses Day 1 PK Summary 300 Mean 6,560.73 SD 1,688.07 CV % 25.7% Geom.Mean 6,293.65 Lower 90% CI 3,630.22 Upper 90% CI 10,911.21 450 Mean8,959.13 SD 2,397.56 CV %   27% Geom. Mean 8,382.03 Lower 90% CI3,795.01 Upper 90% CI 18,513.38 600 Mean 9,990.20 SD 2,577.37 CV%   26%Geom. Mean 9,644.67 Lower 90% CI 5,962.46 Upper 90% CI 15,600.89 Day 5PK Summary 300 Mean 9,351.02 SD 2,461.74 CV % 26.3% Geom. Mean 8,990.55Lower 90% CI 5,358.92 Upper 90% CI 15,083.28 450 Mean 13,363.54 SD3,469.26 CV % 26.0% Geom. Mean 12,883.95 Lower 90% CI 7,849.02 Upper 90%CI 21,148.66 600 Mean 16,171.61 SD 4,501.33 CV % 27.8% Geom. Mean15,431.37 Lower 90% CI 8,683.23 Upper 90% CI 27,423.79

Using pharmacokinetic data from this and other Phase 1 studies, PKmodels for the following dosing regimens have been constructed, and theresults were presented in FIGS. 2-4.

Specifically, FIG. 2 showed PK data for a dosing regimen, in which 100mg of omadacycline was administered i.v. BID (twice a day, administered12 hrs apart) for 1 day, followed by 100 mg i.v./day).

FIG. 3 showed PK data for a dosing regimen, in which 450 mg ofomadacycline was administered p.o. QD (once a day) for 2 days, followedby 300 mg p.o./day.

FIG. 4 showed PK data for a dosing regimen, in which 600 mg ofomadacycline was administered p.o. QD (once a day) for 2 days, followedby 300 mg p.o./day.

It is apparent that AUC₀₋₂₄ for the dosing regimens shown in FIGS. 2 and3 were nearly identical.

More detailed data analysis were presented below.

At all tested omadacycline dose levels on both Day 1 and Day 5 of each5-day treatment period, mean plasma omadacycline concentrations peaked2.5 hours after dosing (T_(max)) and omadacycline was measurable inplasma for up to 24 hours after dosing (the last sampling time) (FIG. 5and Table 2-2).

TABLE 2-2 Plasma Pharmacokinetic Parameters of Omadacycline by Dose onDays 1 and 5 of Dosing^(a) Omadacycline Dose Day 1 Day 5 300 mg 450 mg600 mg 300 mg 450 mg 600 mg Parameter (n = 25) (n = 24) (n = 24) (n =23) (n = 24) (n = 23) Mean AUC₀₋₂₄, 6644.8 8976.5 10020.5 9267.2 13366.716420.3 ng · h/mL (CV) (25.3) (26.6) (25.7) (26.8) (26.0) (27.1) MeanC_(max), ng/mL 648.8 874.2 954.5 808.8 1077.3 1305.5 (CV) (24.0) (26.6)(23.2) (25.9) (25.0) (26.6) Mean T_(max), h 2.50 2.50 2.51 2.50 2.502.50 (Min, max) (1.50, 3.00) (1.50, 3.00) (1.00, 3.00) (1.00, 3.00)(1.50, 4.00) (2.00, 4.00) Mean T_(1/2), h 13.66 13.45 13.03 15.49 16.8316.75 (CV)  (12.5)^(b)  (12.9)^(c)  (11.8)^(c)  (10.7)^(d)  (8.1)^(c) (6.8)^(d) ^(a)Results for Pharmacokinetic Population ^(b)n = 24(T_(1/2) was not estimable for 1 subject) ^(c)n = 23 (T_(1/2) was notestimable for 1 subject) ^(d)n = 21 (T_(1/2) was not estimable for 2subjects) CV, coefficient of variation Note: One 300 mg omadacyclinesubject and one 600 mg omadacycline subject were excluded from the Day 5summary due to vomiting before reaching the pharmacokinetic steady stateon Day 5

Omadacycline total exposure (AUC₀₋₂₄ and AUC_(last)) and peakconcentrations (C_(max)) increased with increasing omadacycline dose(300 vs 450 vs 600 mg) on both Day 1 and Day 5, and were higher on Day 5than on Day 1 for corresponding doses (FIG. 5 and Table 2-2). The meanhalf-life of omadacycline in plasma (T_(1/2)) was similar across the 3tested dose levels, ranging from 13.03 to 13.66 hours on Day 1 and from15.49 to 16.83 hours on Day 5 (Table 2-2). Between-subject variabilityin systemic omadacycline exposure was low and was similar at all threetested dose levels, with coefficients of variation (CVs) ranging from23.2% to 26.6% for C_(max), AUC₀₋₂₄, and AUC_(last) on Day 1 and from25.0% to 27.1% for C_(max), AUC₀₋₂₄, and AUC_(last) on Day 5 (Table2-2).

Although omadacycline AUC₀₋₂₄, AUC_(last) and C_(max) increased withincreasing omadacycline dose, the observed increases in exposure wereless than dose proportional on both days of analysis (Tables 2-2 and2-3).

TABLE 2-3 Statistical Analysis of Dose-Normalized OmadacyclinePharmacokinetic Parameters on Days 1 and 5 of Dosing^(a) Ratio ofGeometric Geometric Treatment LS Means 90% CI of Parameter Treatment NLS Means Comparison (%) Ratio (%) Day 1 AUC₀₋₂₄/Dose 300 mg 25 21.32450/300 87.44  (77.41, 98.77) (ng · h/mL/mg) 450 mg 24 18.64 600/45086.79  (76.71, 98.20) 600 mg 24 16.18 600/300 75.89  (67.20, 85.71)C_(max)/Dose 300 mg 25 2.09 450/300 86.71  (76.17, 98.71) (ng/mL/mg) 450mg 24 1.81 600/450 85.26  (74.76, 97.23) 600 mg 24 1.54 600/300 73.92 (64.95, 84.14) Day 5 AUC₀₋₂₄/Dose 300 mg 23 30.09 450/300 95.82 (90.39,101.59) 24 28.83 (ng · h/mL/mg) 450 mg 23 26.46 600/450 91.78  (86.58,97.30) 600 mg 600/300 87.95  (82.96, 93.25) C_(max)/Dose 300 mg 23 2.62450/300 88.58  (83.19, 94.32) (ng/mL/mg) 450 mg 24 2.32 600/450 90.72 (85.20, 96.60) 600 mg 23 2.11 600/300 80.36  (75.47, 85.58) ^(a)Resultsfor Pharmacokinetic Population ANOVA analysis; see Materials and Methodsfor details CI, confidence interval; LS, least squares Note: One 300 mgomadacycline subject and one 600 mg omadacycline subject were excludedfrom the Day 5 statistical analysis due to vomiting before reaching thepharmacokinetic steady state on Day 5

Statistical analyses showed that with an increase in dose from 300 mg to600 mg, omadacycline exposure (based on dose-normalized AUC₀₋₂₄) on Day1 was 76% of that predicted if exposure were perfectly dose-proportional(Table 2-3); on Day 5, the observed increase in omadacycline exposurewas 88% of predicted (Table 2-3). Analysis of C_(max) values similarlydemonstrated that omadacycline concentrations were dose-linear, but lessthan dose-proportional in this study (Tables 2-2 and 2-3).

Statistical analyses also revealed accumulation of omadacycline inplasma following once-daily dosing for 5 consecutive days. Depending ondose, accumulation ratios between Day 5 and Day 1 ranged from 1.40 to1.62 for AUC₀₋₂₄ and from 1.24 to 1.35 for C_(max) (data not shown).These findings are consistent with the long half-life of omadacycline inplasma.

The above data showed that mean concentrations of omadacycline peaked at2.5 hours and remained measurable up to 24 hours (the last tested timepoint) at all omadacycline dosing levels (300, 450, and 600 mg). On Day5, mean steady state exposure (AUC₀₋₂₄) in subjects dosed with 300-mgomadacycline was 9267 ng·h/mL, which is consistent with results ofprevious studies with 300 mg oral dosing. Both AUC₀₋₂₄ and C_(max)increased with increasing dose and were nearly, but somewhat less than,dose-proportional (74%-88% of expected). This was the case on both Day 1and Day 5 of dosing. Due to its relatively long half-life (mean=˜13 h onDay 1, ˜16 h on Day 5), omadacycline accumulated in plasma over thecourse of 5 consecutive days of dosing. Thus, at all tested dose levels,systemic exposure on Day 5 was ˜50% higher than on Day 1. This degree ofaccumulation is also consistent with that observed following multipleonce-daily dosing of IV or oral formulations of omadacycline in earlypharmacology studies.

In terms of systemic exposure, this study showed that omadacyclineplasma concentrations on Day 1 of 450-mg dosing were similar to those onDay 5 of 300-mg dosing (mean AUC₀₋₂₄=8976.5 and 9267.2 ng·h/mL,respectively). For indications in which the therapeutic dosing regimenincorporates 300 mg daily oral dosing, these data support a strategy ofusing an initial oral “loading dose” of 450 mg once-daily for 1-2 days,followed by 300-mg once-daily oral dosing. Such a strategy couldpotentially eliminate the need for an IV phase of treatment and iscurrently being evaluated in an ongoing phase 3 trial of oral-onlyomadacycline treatment in patients with ABSSSI (ClinicalTrials.gov ID,NCT02877927).

c. Urine Pharmacokinetics

Because urine sample collection and PK analysis were added to the studyby protocol amendment after the study was underway, only a limitednumber of samples were evaluated (samples from 9 subjects on Day 5 ofPeriod 2 and samples from 8 subjects on Day 1 and Day 5 of Period 3).While this sample size was too small to make meaningful comparisonsbetween omadacycline dose groups, the results of the analysis didprovide an overall indication of partial omadacycline renal clearanceand urinary excretion.

For all omadacycline dose groups, the mean fraction of the dose excretedunchanged in urine from 0 to 24 hours after dosing (Fe₀₋₂₄) ranged from˜5% to ˜7% on Day 1 and from ˜7% to −9% on Day 5. Renal clearance (CLr)ranged from 2.8 to 4.2 L/h on Day 1 and from 2.4 to 3.3 L/h on Day 5(Table 2-4).

TABLE 2-4 Urine Pharmacokinetic Parameters of Omadacycline by Dose onDays 1 and 5 of Dosing^(a) Omadacycline Dose Day 1 Day 5 300 mg 450 mg600 mg 300 mg 450 mg 600 mg Parameter^(b) (n = 2) (n = 3) (n = 1) (n =3) (n = 5) (n = 4) Ae₀₋₂₄ (mg) 20.37 (8.3) 25.06 (16.8) 31.96 26.14(14.6) 30.81 (33.0) 51.82 (14.8) Fe₀₋₂₄ (%)  6.79 (8.3)  5.57 (16.8)5.33  8.71 (14.6)  6.85 (33.0)  8.64 (14.8) CLr (L/h) 3.01 (11.4)  2.80(9.6) 4.17  3.28 (27.2)  2.38 (34.9)  3.05 (19.9) ^(a)Results forPharmacokinetic Population ^(b)Mean (CV) CV, coefficient of variationNote: One 600 mg omadacycline subject was excluded from the summary dueto vomiting before reaching the pharmacokinetic steady state on Day 5

Urine PK analyses in a subset of subjects provided preliminaryindications of partial renal clearance and urinary excretion ofomadacycline. On Day 5, depending on dose level, ˜7% to ˜9% of theadministered oral dose was excreted unchanged in the urine over 24hours. This represents approximately 20% to 25% of the absorbed dosesince it is known that the absolute bioavailability of the tabletformulation used in this study is 35%. Presence of unchangedomadacycline in the urine suggests that it may be useful in urinarytract infections, an indication that is currently being explored.

d. Safety and Tolerability

Overall, 12 of the 33 subjects in the safety population reported a totalof 36 TEAEs during the study (Table 2-5).

TABLE 2-5 Summary of Treatment-Emergent Adverse Eventsa Omada-Omadacycline Dose cycline Placebo 300 mg 450 mg 600 mg Overall Overall(n = 26) (n =24) (n = 24) (n = 26) (n = 7) n (%) of subjects with: AnyTEAE 5 (19.2) 3 (12.5) 6 (25.0) 10 (38.5) 2 (28.6) Treatment- 4 (15.4) 2(8.3) 6 (25.0) 9 (34.6) 1 (14.3) related TEAE Most frequent TEAEs (seenin >1 study subject), n (%) Nausea 2 (7.7) 1 (4.2) 4 (16.7) 6 (23.1) 0Vomiting 2 (7.7) 0 1 (4.2) 3 (11.5) 0 Diarrhea 0 0 2 (8.3) 2 (7.7) 0Dizziness 2 (7.7) 0 1 (4.2) 3 (11.5) 0 ALT increased 0 1 (4.2) 1 (4.2) 2(7.7) 0 TEAEs leading to early discontinuation of study drug, n (%) All1 (3.8) 1 (4.2) 1 (4.2) 3 (11.5) 1 (14.3) Nausea 1 (3.8) 0 0 1 (3.8) 0Vomiting 1 (3.8) 0 0 1 (3.8) 0 ALT increased 0 1 (4.2) 0 1 (3.8) 0Lipase increased 0 0 1 (4.2) 1 (3.8) 0 Syncope 0 0 0 0 1 (14.3)^(b)^(a)Results for Safety Population ^(b)vasovagal syncope following ablood draw ALT, alanine aminotransferase; TEAE, treatment-emergentadverse event

TEAEs were reported by 38.5% of subjects that received omadacycline and28.6% of subjects that received placebo. The highest percentage of TEAEswas classified as gastrointestinal (GI) disorders. The most frequentlyreported TEAE was nausea, which occurred in ≤7.7% of the omadacycline300 and 450 mg dose groups and 16.7% of the 600 mg group.

All of the TEAEs reported in this study were either mild or moderate inseverity. There were no serious TEAEs (SAEs) reported during the study.Four subjects experienced TEAEs leading to study discontinuation,including one subject at each of the 3 omadacycline dose levels and 1subject in the placebo group.

There were no clinically significant findings in analyses of vital signmeasurements, physical examination, ECG results, hematology orurinalysis parameters. Serum chemistry analyses showed that betweenbaseline and Day 5 of each dosing period, the median change in alanineaminotransferase (ALT) concentration was −2.0, 5.0 and 19.5 IU/L insubjects dosed with 300, 450 and 600 mg omadacycline, respectively. Thecorresponding changes in placebo groups ranged from −5.0 to −1.0 IU/L.No substantial changes in median aspartate aminotransferase (AST),bilirubin or other serum chemistry parameters were noted. The highestindividual ALT value was 150 IU/L (2.7-fold above the upper limit ofnormal [ULN]), which occurred in a subject who first received 450 mgomadacycline in Period 1 then 300 mg in Period 2 and then wasdiscontinued due to the liver enzyme changes; this subject's bilirubinvalues remained within the normal range at all time points assessed.

The plasma PK findings indicate that higher systemic drug exposure canbe achieved by increasing the amount of omadacycline administered perdose during once-daily oral dosing, but that the exposure benefit is notdose-proportional. Moreover, increasing omadacycline dosing beyond acertain point appears to have adverse effects in terms of safety andtolerability. While multiple doses of 300, 450, and 600 mg were allgenerally well-tolerated in this study (all TEAEs were either mild ormoderate in severity), there were some differences between the doses.The frequency of treatment-related TEAEs did not increase with anincrease in omadacycline dose from 300 to 450 mg (15.4% vs 8.3%), butsuch events were more frequent with 600 mg (25.0%). Within the mostfrequent class of TEAEs, GI disorders, nausea occurred with incidence atleast 9% higher for the 600 mg dose level than for the lower doses, andthe only 2 reports of diarrhea occurred with 600 mg. In addition, serumchemistry analyses showed a small but notable dose-dependent increase inmedian ALT concentrations. While no individual ALT values exceeded3-fold above the ULN, the higher median ALT at 600 mg suggests anincreased chance of more significantly elevated serum transaminaselevels with this dose. Based on these findings, for situations in whichan oral dose above 300 mg may be beneficial, 450 mg was identified asthe oral dose most likely to provide higher omadacycline exposure withfavorable safety and tolerability.

In summary, this phase 1 study investigated the pharmacokinetics (PK)and safety/tolerability of multiple oral omadacycline doses higher than300 mg. Using a 3-period crossover design, healthy adults wererandomized to receive omadacycline (300-, 450- and 600-mg in variablesequence; n=26) or placebo (n=7) once daily for 5 consecutive days perperiod. In plasma, omadacycline maximum concentration and total exposureincreased with increasing dose, but were less than dose-proportional(74% to 88% of expected). The kinetics of omadacycline plasmaaccumulation were similar between dose levels; exposure on Day 5 was˜50% higher than on Day 1. Omadacycline plasma concentrations on Day 1of 450 mg dosing were similar to those on Day 5 of 300 mg dosing. UrinePK analyses indicated partial renal clearance and urinary excretion ofunchanged omadacycline. All doses were generally well-tolerated. Theseresults support the use of once-daily 450-mg oral omadacycline as partof the oral only dosing regimen, such as using once-daily 450-mg oralomadacycline (either one or two doses) as loading dose before steppingdown to once-daily 300-mg oral omadacycline, or in a dosing regimenusing once-daily 450-mg oral omadacycline throughout the treatment.

Example 3 A Phase 3 Randomized, Double-Blind, Multi-Center Study toCompare the Safety and Efficacy of Oral Omadacycline to Oral Linezolidfor Treating Adult Subjects with Acute Bacterial Skin and Skin StructureInfection (ABSSSI)

9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, otherwise known asomadacycline (OMC), the first aminomethylcycline antibiotic, is asemi-synthetic derivative of the tetracycline class. As a class, thetetracyclines have been in use for approximately 70 years. They arewell-tolerated, and have proven effective in the treatment of a varietyof bacterial infections.

Omadacycline has demonstrated activity against the most common ABSSSIpathogens, including methicillin-resistant Staphylococcus aureus (MRSA).Omadacycline was evaluated in a Phase 2 study of 219 subjects withcomplicated skin and skin structure infection (cSSSI) and asponsor-terminated Phase 3 study of 140 subjects with cSSSI.Omadacycline was well-tolerated and demonstrated efficacy similar to anestablished comparator (linezolid).

In a recently completed global Phase 3 study of 645 subjects comparingthe safety and efficacy of intravenous (i.v.) and per oral (p.o.)omadacycline to i.v. and p.o. linezolid in the treatment of adultsubjects with ABSSSI, omadacycline was non-inferior to linezolid and waswell tolerated.

I. Study Design

This was a Phase 3 study designed to demonstrate the safety and efficacyof p.o. omadacycline as compared to p.o. linezolid in the treatment ofadult subjects with ABSSSI. Specifically, the study was designed todemonstrate that omadacycline administered orally (p.o.) for 7 to 14days is (10%) non-inferior to linezolid administered orally for 7 to 14days in the treatment of adult subjects with ABSSSI known or suspectedto be due to Gram-positive pathogens. In addition, the study wasdesigned to demonstrate that omadacycline is safe in treating adultsubjects with ABSSSI; and that the observed Clinical Response is due toneutralizing the identified causative pathogen of ABSSSI. Finally, thepharmacokinetics (PK) of oral omadacycline was evaluated in these inadult subjects.

The experiment was designed as a randomized (1:1), double-blind,double-dummy, active comparator-controlled, Phase 3 study comparingomadacycline and linezolid for the treatment of adult subjects withABSSSI that was known or suspected to be due to a Gram-positivepathogen(s). Enrollment of subjects with major abscess may be up to 30%of randomized subjects. Enrollment of subjects who had received a singledose of an allowed short-acting antibiotic within the 72 hours prior torandomization were limited to no more than 25% of randomized subjects.Subject randomization was stratified across treatment groups by type ofinfection (wound infection, cellulitis/erysipelas, or major abscess) andreceipt of a prior allowed short-acting antibiotic (yes or no).

The study consisted of 3 protocol-defined phases: Screening,Double-Blind Treatment, and Follow-up. All Screening evaluations, withthe exception of the blood culture, was completed within the 24 hoursprior to randomization. The blood culture was completed within the 24hours prior to the first dose of test article. Subjects who metinclusion criteria, and did not meet exclusion criteria, were randomlyassigned to a treatment group, and received their first dose of testarticle (either omadacycline or linezolid) at the site within 4 hoursafter randomization.

The study was designed in accordance with the U.S. FDA and EuropeanMedicines Agency (EMA) guidance on developing antimicrobial drugs forthe treatment of ABSSSI, in addition to the guidelines of the InfectiousDiseases Society of America (IDSA) and 2012 Update from the BiomarkersConsortium of the Foundation for the National Institutes of Health.

The comparator drug, linezolid, has been approved world-wide for thetreatment of ABSSSI caused by Gram-positive pathogens and has anacceptable and well-defined safety profile. Linezolid can beadministered orally, and has regulatory approval for the treatment ofABSSSI caused by Gram-positive pathogens including MRSA.

Subjects participated in the study for approximately 30 days. FollowingScreening, eligible subjects were randomly assigned to receive 7 to 14days of p.o. treatment with either omadacycline or linezolid. Afollow-up office visit occurred approximately 7 to 14 days after thelast dose of test article, and a follow-up telephone contact occurredapproximately 30 to 37 days after the first dose of test article.

To be eligible for randomization in this study, other than informedconsent, an eligible subject fulfilled all of the following keycriteria: (1) male or female, age 18 years or older; (2) had aqualifying skin and skin structure infection. For the purpose of theclinical trial, all qualifying lesions were greater than or equal to 75cm² in total surface area of contiguous involved tissue, calculated asthe product of the maximum length (head-to-toe) multiplied by themaximum width (measured perpendicular to length) as measured by theinvestigator using a wound ruler. Involved tissue was defined as tissueexhibiting clear evidence of one or more of the following: erythema,edema or induration; (3) the classification of qualifying infectionswas: wound infection—an infection characterized by purulent drainagefrom a wound with surrounding erythema, edema, and/or indurationextending at least 5 cm in the shortest distance from the peripheralmargin of the wound; Cellulitis/erysipelas—a diffuse skin infectioncharacterized by spreading areas of erythema, edema, and/or induration;Major abscess—an infection characterized by a collection of pus withinthe dermis or deeper with surrounding erythema, edema, and/or indurationextending at least 5 cm in the shortest distance from the peripheralmargin of the abscess; (4) had evidence of a systemic inflammatoryresponse within the 24 hours prior to randomization, as indicated by ONEof the following: elevated white blood cell (WBC) count (greater than orequal to 10,000 cells/mm³) or leukopenia (less than or equal to 4,000cells/mm³); elevated immature neutrophils (greater than or equal to 15%band forms) regardless of total peripheral WBC count; lymphaticinvolvement: lymphangitis or lymphadenopathy that was proximal to and ina location that suggested drainage from the qualifying infection; andfever or hypothermia documented by the investigator (temperature greaterthan 38.0° C. [100.4° F.] or less than 36.0° C. [95.5° F.]).

During the screening phase, subject eligibility and baselinecharacteristics (based on a comprehensive history and physicalexamination, paying particular attention to medical history relating tothe infection under study) for each subject were established. Subjectswere eligible for Screening if they presented with ABSSSI signs andsymptoms. For example, at the screening evaluation, the type of ABSSSIwas recorded: wound infection, cellulitis/erysipelas or major abscess asdefined in the inclusion criteria. To qualify, there must be greaterthan or equal to 75 cm² in total surface area of contiguous involvedtissue (i.e., surrounding erythema, edema and/or induration).

The anatomical location of the primary site of infection was alsorecorded. For subjects with multiple non-contiguous areas of infection,the most severely affected portion was identified at Screening and wasdesignated as the primary lesion site. The presence and nature of anyforeign body (e.g., wood, metal, plastic, etc.) present at the site ofinfection was noted. The following information regarding the primarysite of infection was recorded: presence of lymphadenopathy proximal toprimary lesion site; and presence of lymphangitis proximal to primarylesion site; presence of drainage from the primary lesion site anddescription (serous/serosanguineous, seropurulent, or purulent).Semi-quantitative (none, mild, moderate, severe) description ofinfection for the following features was also provided: tenderness,edema, erythema, & induration.

The Screening evaluation measurement of lesion size was collected within4 hours prior to randomization. Surface area of lesions was calculatedby multiplying the head-to-toe maximum length of the total lesion andmaximum width (perpendicular to maximum length) inclusive of contiguousinvolvement (erythema, edema and/or induration). Investigator rulermeasurements could be used to document the lesion size.

In addition, each subject was asked to report certain outcomes orparameters related to disease status and treatment efficacy, such asNumerical Rating Scale for Pain (0-10) at the primary ABSSSI lesionsite; SF-36v2® Health Survey (which was referred to as a generic healthsurvey because it can be used across age (18 and older), disease, andtreatment group, as opposed to a disease-specific health survey, whichfocuses on a particular condition or disease). In addition, a urinedipstick was performed locally at Screening.

Subjects who met inclusion criteria, and did not meet exclusion criteriawere randomly assigned to a treatment group, and received their firstdose of test article at the site within 4 hours after randomization.

Subjects were randomized (1:1) to 1 of the following 2 treatment arms:

-   -   Investigational therapy: omadacycline, 450 mg p.o. every 24        hours (q24h) for 2 doses, followed by 300 mg p.o. q24h. Total        treatment duration of 7 to 14 days.    -   Reference therapy: linezolid, 600 mg p.o. every 12 hours (q12h).        Total treatment duration of 7 to 14 days.

The study employed a double-blind, double-dummy design usingomadacycline placebo comparator tablets of matching size and shape toactive omadacycline tablets and matching over-encapsulated placebo andover-encapsulated active linezolid tablets. To maintain double blinding,subjects on both arms received the same number of tablets.

The double-blind treatment period, according to the instant Experiment,was designed to be 7 to 14 days in duration. The following tablesummarizes actual study drug exposure in the safety population:

Omadacycline Linezolid (N = 368) (N = 367) Characteristics n (%) n (%)Duration of exposure on therapy (days) n 368 367 Mean (SD) 8.2 (2.77)8.0 (2.98) Median 8.0 7.0 Min, Max 1, 14 1, 17 Duration of exposure ontherapy (days), n (%) n 368 367 1-3 30 (8.2) 40 (10.9) 4-6 11 (3.0) 12(3.3)  7-10 286 (77.7) 278 (75.7) 11-12 12 (3.3) 6 (1.6) 13-14 29 (7.9)26 (7.1) >14 0 5 (1.4) Percentages for duration of exposure were basedon subjects receiving at least one dose. Duration of study drug exposurein days = date of last dose-date of first dose + 1.

All doses of test article were taken with water. There were fastingrequirements for administration of the odd numbered doses due to effectsof food on oral omadacycline. These fasting requirements were consideredwhen determining the time of day when subjects took their doses.

II. Efficacy and Evaluation

Subjects were evaluated at 2 visits after the completion of treatment:at the PTE (Post Therapy Evaluation) visit, 7 to 14 days after thesubject's last day of study therapy, and at a Final Follow-upassessment, 30 to 37 days after the first dose of treatment. The FinalFollow-up assessment could be conducted via telephone contact or byanother interactive technology for subjects who were considered to beClinical Successes and had no AEs or clinically significant laboratoryor ECG abnormalities noted at or after the PTE visit. Otherwise, thisassessment was performed with an in person study visit.

Efficacy analysis was based on the following list of key assessments:

-   -   Clinical assessment of the site of infection    -   Assessment of lesion size    -   Assessment of the need for adjunct surgical procedures    -   Microbiological assessment of the infection    -   Assessment of clinical response by the investigator    -   Assessment of all-cause mortality

Each is described in further detail below.

a. Clinical Assessment of the Site of Infection

The clinical assessment of the site of infection was conducted atScreening and every scheduled evaluation with the exception of the FinalFollow-up assessment. A clinical assessment of the site of infection wasperformed within 48 to 72 hours after the first dose. The primary siteof infection was examined, and the following information was recorded:presence of drainage from the primary lesion site and description(serous/serosanguineous, seropurulent, or purulent); andsemi-quantitative (none, mild, moderate, severe) description ofinfection for the following features—tenderness; edema; erythema; andinduration.

b. Assessment of Lesion Size

Lesion measurements by ruler was performed at Screening, and everyscheduled evaluation with the exception of the Final Follow-upassessment.

Surface area of lesions was calculated by multiplying the head-to-toemaximum length of total lesion and maximum width (perpendicular tomaximum length) inclusive of contiguous involvement (erythema, edemaand/or induration). Investigator ruler measurements were used todocument lesion size.

c. Microbiological Assessment of the Site of Infection

At the Screening visit, material was collected from the site ofinfection and submitted to site's local microbiology laboratory for Gramstain and culture. The type of specimen submitted was recorded.Laboratory reports on Gram stains included a semi-quantitativedescription of the number of polymorphonuclear leukocytes per low powerfield (i.e., 100×) and a description of bacteria seen. Blood cultureswere also performed to assess concurrent bacteremia.

As the site of infection responded to therapy, repeated cultures may notbe clinically appropriate and/or there may be no material for culture.At the EOT and/or PTE visit, infection site specimen cultures and Gramstains were obtained only for subjects who were clinical failures andrequire alternative antibacterial treatment for the infection understudy.

All specimens submitted to the site's local laboratory were evaluatedfor aerobic and, where appropriate, anaerobic culture. Culture resultsincluded a semi-quantitative description of the organisms on the primaryculture plate and identification of all isolates to the level of genusand species. Susceptibility testing for linezolid was performed locallyusing a standard method chosen by the laboratory. Results of thistesting were used along with clinical findings to help guide therapy.

All bacterial isolates identified from infection site specimens or bloodwere submitted to the Central Laboratory for verification of genus andspecies and for standardized minimum inhibitory concentration (MIC)testing performed for omadacycline, linezolid and a panel of currentlyapproved antibiotics.

If there was evidence of a Gram-negative or anaerobic microorganism, ormicroorganism that was non-susceptible to linezolid, the decision tocontinue or discontinue test article and change the antibacterialregimen was made based on the investigator's clinical judgment and wererecorded in the source documents.

d. Assessment of Clinical Outcome

Assessment of clinical outcome occurred at the Early Clinical Responseassessment (programmatically), EOT, and PTE as described below.

i) Evaluation of the Infection Under Study at the Early ClinicalResponse Assessment

The formal determination of the response to therapy at the EarlyClinical Response assessment (48 to 72 hours after the first dose oftest article) was done programmatically using lesion measurement values.

“Clinical Success” at the Early Clinical Response assessment was definedas meeting all 3 of the following: the subject was alive; the size ofthe primary lesion had been reduced greater than or equal to 20%compared to Screening measurements, without receiving any alternative(rescue) antibacterial therapy; and the subject did not meet anycriteria for Clinical Failure or Indeterminate (see below fordefinitions).

“Clinical Failure” was defined as meeting any of the criteria below: thesize of the primary lesion had not been reduced by greater than or equalto 20% compared to Screening measurements; test article was discontinuedbased on the determination that the infection had responded inadequatelysuch that alternative (rescue) antibacterial therapy was needed; thesubject received antibacterial therapy that may be effective for theinfection under study for a different infection from the one understudy; the subject developed an AE that required discontinuation of testarticle prior to the Early Clinical Response assessment and alternative(rescue) antibacterial therapy was needed; or death prior to EarlyClinical Response assessment.

“Indeterminate” was given when the clinical response to test articlecould not be adequately inferred because: subject was not seen for EarlyClinical Response assessment because they withdrew consent, were lost tofollow-up, or other reasons.

ii) Clinical Evaluation of the Infection Under Study at EOT

At the EOT visit (on the day of or within 2 days following the last doseof test article), the clinical status of the infection under wasindicated as detailed below.

“Clinical Success” at the End of Treatment (EOT) assessment was definedas meeting the following: the subject was alive; and the infection wassufficiently resolved such that further antibacterial therapy was notneeded (these subjects might have some residual changes related toinfection requiring ancillary (i.e., non-antibiotic) treatment, e.g.,bandages on a healing wound, debridement of uninfected tissue (i.e.,necrotic)).

Clinical Failure was defined as meeting any of the criteria below, theprimary reason for clinical failure was designated: test article wasdiscontinued based on the determination that the infection had respondedinadequately such that alternative (rescue) antibacterial therapy wasneeded; the subject received antibacterial therapy that may be effectivefor the infection under study for a different infection from the oneunder study; or the subject developed an AE that requireddiscontinuation of test article prior to completion of the planned testarticle regimen and alternative (rescue) antibacterial therapy wasneeded; unplanned major surgical intervention (i.e., procedures thatwould not normally be performed at the bedside) for the infection understudy; the subject died before evaluation; or others.

“Indeterminate” was given if the clinical response to test article couldnot be adequately inferred. All that apply are marked: The subject wasnot seen for EOT assessment because they withdrew consent, were lost tofollow-up, or other reason.

iii) Clinical Evaluation of the Infection Under Study at PTE

At the Post Therapy Evaluation PTE visit (7 to 14 days after thesubject's last day of study therapy), ONE of the following outcomesrelating to the primary infection under study was indicated:

“Clinical Success” at the Post Therapy Evaluation assessment was definedas meeting the following: the subject was alive; the infection wassufficiently resolved such that further antibacterial therapy was notneeded (these subjects might have some residual changes related toinfection requiring ancillary (i.e., non-antibiotic) treatment, e.g.,bandages on a healing wound, debridement of uninfected tissue (i.e.,necrotic).

“Clinical Failure” was defined as meeting any of the criteria below, theprimary reason for clinical failure was designated: the infectionrequired additional treatment with alternative (rescue) antibacterialtherapy; the subject received antibacterial therapy between EOT and PTEthat may be effective for the infection under study for a differentinfection from the one under study; unplanned major surgicalintervention (i.e., procedures that would not normally be performed atthe bedside) for the infection under study between EOT and PTE; thesubject died before evaluation; and others.

“Indeterminate” was given when the clinical response to test articlecould not be adequately inferred. All that apply were marked: thesubject was not seen for PTE assessment because they withdrew consent,were lost to follow-up, and other reason.

III. Pharmacokinetic Studies

PK data was analyzed using a population PK model. Blood samples werecollected for PK analysis using a sparse sampling method for thepopulation PK model. The number of samples and collection schedule varyfor individual subjects. Up to 4 blood samples were collected persubject between Days 2 and 3. Blood was collected either by freshvenipuncture or via a cannula used solely for that purpose. The datesand times for all doses of test article and PK sample collections wererecorded. The identification of the subject, sample number and the timeof the sample collection to the nearest minute were immediately recordedon the collection tube. The tube was centrifuged at 1500×g for 10minutes; the separated plasma transferred in 2 equal aliquots intopre-labeled tubes; and the tubes frozen at −70° C. within 60 minutes ofcollection. The time the sample was frozen was recorded to the nearestminute.

The samples for omadacycline were analyzed using a specific, sensitiveand validated Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS)method.

IV. Safety Monitoring

An Adverse Event (AE) is any untoward, undesired, or unplanned event inthe form of signs, symptoms, disease, or laboratory or physiologicobservations occurring in a person given a test article or in a clinicalstudy. The event does not need to be causally related to the testarticle or clinical study. An AE includes, but is not limited to, thefollowing: any clinically significant worsening of a preexistingcondition; an AE occurring from overdose of a test article, whetheraccidental or intentional; overdose is a dose greater than thatspecified in the protocol; an AE occurring from abuse (e.g., use fornonclinical reasons) of a test article; and an AE that has beenassociated with the discontinuation of the use of a test article.

The severity (or intensity) of an AE was classified using the followingcriteria:

Mild: These events were usually transient, required minimal or notreatment, and did not interfere with the subject's daily activities.

Moderate: These events resulted in a low level of inconvenience orconcern with the therapeutic measures. Moderate events might cause someinterference with normal functioning but posed no significant orpermanent risk of harm.

Severe: These events interrupted a subject's usual daily activity andmight require systemic drug therapy or other treatment. Severe eventswere usually incapacitating.

A Serious Adverse Event (SAE) is an AE that: resulted in death; waslife-threatening (see below); required hospitalization or prolongationof an existing hospitalization (see below); resulted in a persistent orsignificant disability or incapacity (see below); resulted in acongenital anomaly or birth defect; additionally, important medicalevents that may not result in death, be life-threatening, or requirehospitalization may be considered SAEs when, based on appropriatemedical judgment, they might jeopardize the subject and might requiremedical or surgical intervention to prevent any one (1) of the outcomeslisted above in this definition. Examples of such events includeallergic bronchospasm requiring intensive treatment in an emergency roomor at home, blood dyscrasias or convulsions that do not result inhospitalization, or development of drug dependency or drug abuse.

Life-threatening refers to immediate risk of death as the event occurredper the reporter. A life-threatening experience did not include anexperience, had it occurred in a more severe form, might have causeddeath, but as it actually occurred, did not create an immediate risk ofdeath.

Hospitalization is official admission to a hospital. Hospitalization orprolongation of a hospitalization constitutes criteria for an AE to beserious; however, it is not in itself considered an SAE. In absence ofan AE, a hospitalization or prolongation of a hospitalization was notreported as an SAE by the participating investigator. This was the casein the following situations: the hospitalization or prolongation ofhospitalization was needed for a procedure required by the protocol; thehospitalization or prolongation of hospitalization was part of a routineprocedure followed by the center (e.g., stent removal after surgery);and a hospitalization for a preexisting condition that had not worsened.

Disability is defined as a substantial disruption in a person's abilityto conduct normal life functions. If there was any doubt about whetherthe information constitutes an SAE, the information was treated as anSAE.

A subject's AEs and SAEs were recorded and reported from the signing ofthe Informed Consent Form to the time of the Final Follow-up assessment.The subject was instructed to report AEs and SAEs during this timeperiod. Reports of death within 30 days after the last contact with thesubject was reported to the sponsor and additional information relativeto the cause of death was sought and documented.

The subjects were followed-up as medically necessary on all AEs and SAEsuntil the events had subsided, the condition had returned to Baseline,or in case of permanent impairment, until the condition stabilized.

AEs were based on the signs or symptoms detected during the physicalexamination and on clinical evaluation of the subject. If an AE requireda surgical or diagnostic procedure, the illness leading to the procedurewas recorded as the AE, not the procedure itself. Death was recorded asan outcome of an AE. Any unanticipated risks to the subjects werereported promptly.

Concerning relatedness, causality (i.e., whether there was a reasonablepossibility that test article caused the event) for all AEs and SAEs wasassessed. The relationship was characterized using the followingclassification:

-   -   Not related: This relationship suggested that there was no        association between test article and the reported event. The        event could be explained by other factors such as an underlying        medical condition, concomitant therapy, or accident, and no        plausible temporal or biologic relationship existed between test        article and the event.    -   Related: This relationship suggested that a definite causal        relationship existed between test article administration and the        AE, or there was a reasonable possibility that the event was        caused by the study medication, and other conditions (concurrent        illness, progression/expression of disease state, or concurrent        medication reaction) did not appear to explain the event.

AEs and SAEs were also assessed for their potential relationship to theprotocol. A protocol-related adverse event was one that was not relatedto the test article, but was considered by the investigator or themedical monitor (or designee) to be related to the research conditions,i.e., related to the fact that a subject was participating in the study.For example, a protocol-related AE might be an untoward event related toa medical procedure required by the protocol.

The severity (or intensity) of an AE was classified using the followingcriteria:

-   -   Mild: These events were usually transient, required minimal or        no treatment, and did not interfere with the subject's daily        activities.    -   Moderate: These events resulted in a low level of inconvenience        or concern with the therapeutic measures. Moderate events might        cause some interference with normal functioning but posed no        significant or permanent risk of harm.    -   Severe: These events interrupted a subject's usual daily        activity and may require systemic drug therapy or other        treatment. Severe events were usually incapacitating.

Changes in the severity of an AE was documented as a new event to allowan assessment of the duration of the event at each level of intensity tobe performed.

Protocol-defined safety laboratory test results were analyzed as part ofspecific laboratory safety analyses. Additional laboratory test resultsat other time points might be available as part of standard clinicalpractice. Throughout the study, laboratory-related abnormalities wererecorded as AEs only if considered clinically significant, outside therange of expected values given the subject's baseline assessments andclinical course, and not known to be part of another AE diagnosis.

The skin infection that qualified the subject for entry in the study(“qualifying ABSSSI”) was unique because data regarding the progress ofthis infection were being captured as part of efficacy analyses.Therefore, worsening or progression of the qualifying ABSSSI wasrecorded as a clinical failure (as part of the efficacy assessment),rather than an AE, unless the worsening/progression also met thecriteria for a serious AE (in which case the event also was reported asan SAE). In contrast, any new or secondary infections that theinvestigator considered to be distinct from the qualifying ABSSSI (e.g.,a secondary skin abscesses in a different anatomical location) wasreported as AEs in all cases, whether non-serious or serious.

V. Data Analysis

All analyses of data complied with International Conference onHarmonization of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH-E9) and the sponsor's guidancedocuments and standards. Statistical analyses were performed usingStatistical Analysis Software (SAS).

A SAP incorporating the sections below and with mock table, figure andlisting (TFL) shells was prepared prior to the start of the study. Thisplan defined populations for analysis, outlined all data handlingconventions and specified statistical methods to be used for analysis ofsafety and efficacy. As a consequence of differing regulatoryrequirements for the choice of the primary efficacy outcome andstatistical analyses, 2 separate SAPs were prepared (one each for FDAand EMA). The sections below indicate the overall structure and approachof the analyses.

Inferential statistical analyses of the primary and secondary outcomeswere conducted as outlined below. Descriptive statistics, including thenumbers and percentages for categorical variables, and the numbers,means, standard deviations (SD), medians, minimums, and maximums forcontinuous variables were provided. All comparisons were foromadacycline versus linezolid. Exploratory analyses might also beperformed. Listings of individual subject's data were produced.

Analysis Populations

A number of subject analysis populations had been defined for thevarious analyses of efficacy and safety, as follows:

The intent-to-treat (ITT) population consisted of all randomizedsubjects.

The safety population consisted of all randomized subjects who receivedtest article.

The modified intent-to-treat (mITT) population consisted of allrandomized subjects without a sole Gram-negative causative pathogen(s)at Screening.

The microbiological modified intent-to-treat (micro-mITT) populationconsisted of subjects in the mITT population who had at least 1Gram-positive causative pathogen(s) at Screening (e.g., bacterialpathogen identified from a blood culture or from a culture of amicrobiological sample obtained from the primary ABSSSI site atbaseline).

The clinically evaluable (CE) population (CE-PTE and CE-EOT) consistedof all mITT subjects who received at least one dose of test article, hada qualifying ABSSSI, an investigator's assessment of clinical responseat the PTE/EOT visit, with no indeterminate clinical response, and metspecific criteria related to the required assessments.

The microbiologically evaluable (ME) population included subjects in theCE population who had at least 1 Gram-positive causative pathogen(s) atScreening (i.e., all subjects in both the micro-mITT and the CE-PTE/EOTpopulations).

The various subject populations participated in the study, as definedabove, are summarized below:

Omadacycline Linezolid All Subjects Population n (%) n (%) n (%) ITT 368367 735 Safety 368 (100.0) 367 (100.0) 735 (100.0) mITT 360 (97.8) 360(98.1) 720 (98.0) micro-mITT 276 (75.0) 287 (78.2) 563 (76.6) CE-EOT 304(82.6) 296 (80.7) 600 (81.6) CE-PTE 284 (77.2) 292 (79.6) 576 (78.4)ME-EOT 233 (63.3) 229 (62.4) 462 (62.9) ME-PTE 220 (59.8) 225 (61.3) 445(60.5)

Subject disposition in the ITT population is summarized below:

Omadacycline Linezolid All Subjects (N = 368) (N = 367) (N = 735)Parameter/Category n (%) n (%) n (%) p-value Randomized 368 (100.0) 367(100.0) 735 (100.0) Completed Study Treatment^([1]) 328 (89.1) 315(85.8) 643 (87.5) Prematurely Discontinued 40 (10.9) 52 (14.2) 92 (12.5)0.1829 from Study Treatment Reason For Premature Discontinuation fromStudy Treatment Adverse Event 6 (1.6) 4 (1.1) 10 (1.4) Lost to Follow-up18 (4.9) 25 (6.8) 43 (5.9) Withdrawal by Subject 6 (1.6) 8 (2.2) 14(1.9) Physician Decision 3 (0.8) 7 (1.9) 10 (1.4) Death 0 0 0 Other 7(1.9) 8 (2.2) 15 (2.0) Completed Study ^([2]) 314 (85.3) 310 (84.5) 624(84.9) Prematurely Discontinued 54 (14.7) 57 (15.5) 111 (15.1) 0.7583from Study Reason For Premature Discontinuation from Study Adverse Event1 (0.3) 0 1 (0.1) Lost to Follow-up 37 (10.1) 38 (10.4) 75 (10.2)Withdrawal by Subject 11 (3.0) 12 (3.3) 23 (3.1) Physician Decision 0 1(0.3) 1 (0.1) Death 0 0 0 Other 5 (1.4) 6 (1.6) 11 (1.5) * Percentagesare based on the ITT population, p-values for differences betweentreatment groups are from Fisher's exact test. ^([1]) Subjects thatcompleted the study treatment. ^([2]) Subjects that completed the study(i.e., received at least one dose of test article and completed EOT, PTEand Follow-up).

Subject disposition in the mITT population is summarized below:

Omadacycline Linezolid All Subjects Parameter/ (N = 360) (N = 360) (N =720) Category n (%) n (%) n (%) p-value Randomized 360 (100.0) 360(100.0) 720 (100.0) Completed Study Treatment ^([1]) 321 (89.2)  309(85.8)  630 (87.5)  Prematurely Discontinued from Study 39 (10.8) 51(14.2) 90 (12.5) 0.2150 Treatment Reason For Premature Discontinuationfrom Study Treatment Adverse Event 6 (1.7) 4 (1.1) 10 (1.4)  Lost toFollow-up 18 (5.0)  25 (6.9)  43 (6.0)  Withdrawal by Subject 5 (1.4) 7(1.9) 12 (1.7)  Physician Decision 3 (0.8) 7 (1.9) 10 (1.4)  Death 0 0 0Other 7 (1.9) 8 (2.2) 15 (2.1)  Completed Study ^([2]) 306 (85.0)  304(84.4)  610 (84.7)  Prematurely Discontinued from Study 54 (15.0) 56(15.6) 110 (15.3)  0.9175 Reason For Premature Discontinuation fromStudy Adverse Event 1 (0.3) 0 1 (0.1) Lost to Follow-up 37 (10.3) 38(10.6) 75 (10.4) Withdrawal by Subject 11 (3.1)  11 (3.1)  22 (3.1) Physician Decision 0 1 (0.3) 1 (0.1) Death 0 0 0 Other 5 (1.4) 6 (1.7)11 (1.5)  * Percentages are based on the mITT population, p-values fordifferences between treatment groups are from Fisher's exact test.^([1]) Subjects that completed the study treatment. ^([2]) Subjects thatcompleted the study (i.e., received at least one dose of test articleand completed EOT, PTE and Follow-up).

Subject disposition in the CE-PTE population is summarized below:

Omadacycline Linezolid All Subjects Parameter/ (N = 284) (N = 292) (N =576) Category n (%) n (%) n (%) p-value Randomized 284 (100.0) 292(100.0) 576 (100.0) Completed Study Treatment ^([1]) 277 (97.5)  283(96.9)  560 (97.2)  Prematurely Discontinued from Study 7 (2.5) 9 (3.1)16 (2.8) 0.8012 Treatment Reason For Premature Discontinuation fromStudy Treatment Adverse Event 3 (1.1) 2 (0.7) 5 (0.9) Lost to Follow-up1 (0.4) 1 (0.3) 2 (0.3) Withdrawal by Subject 0 1 (0.3) 1 (0.2)Physician Decision 1 (0.4) 4 (1.4) 5 (0.9) Death 0 0 0 Other 2 (0.7) 1(0.3) 3 (0.5) Completed Study ^([2]) 275 (96.8)  287 (98.3)  562 (97.6) Prematurely Discontinued from Study 9 (3.2) 5 (1.7) 14 (2.4)  0.2899Reason For Premature Discontinuation from Study Adverse Event 1 (0.4) 01 (0.2) Lost to Follow-up 8 (2.8) 4 (1.4) 12 (2.1)  Withdrawal bySubject 0 1 (0.3) 1 (0.2) Physician Decision 0 0 0 Death 0 0 0 Other 0 00 * Percentages are based on the CE-PTE population, p-values fordifferences between treatment groups are from Fisher's exact test.^([1]) Subjects that completed the study treatment. ^([2]) Subjects thatcompleted the study (i.e., received at least one dose of test articleand completed EOT, PTE and Follow-up).

Demographic and baseline characteristics of the safety population issummarized below:

Omadacycline Linezolid All Subjects Characteristics (N = 368) (N = 367)(N = 735) p-value Gender n (%) n 368 367 735 Female 126 (34.2) 147(40.1) 273 (37.1) Male 242 (65.8) 220 (59.9) 462 (62.9) 0.109 Race n (%)n 368 367 735 White 327 (88.9) 341 (92.9) 668 (90.9) Black or AfricanAmerican 22 (6.0) 13 (3.5) 35 (4.8) Asian  3 (0.8)  5 (1.4)  8 (1.1)American Indian or Alaska  7 (1.9)  3 (0.8) 10 (1.4) Native NativeHawaiian or Other  3 (0.8) 0  3 (0.4) Pacific Islander Other  6 (1.6)  5(1.4) 11 (1.5) 0.176 Ethnicity n (%) n 368 367 735 Hispanic or Latino154 (41.8) 156 (42.5) 310 (42.2) Not Hispanic or Latino 214 (58.2) 211(57.5) 425 (57.8) Not Reported/Unknown 0 0 0 0.881 Age (years) n 368 367735 Mean (SD)  42.8 (12.72)   44.5 (13.11)   43.7 (12.94)  Median 41.046.0 43.0 Min, Max 18, 86 20, 84 18, 86 0.109 Categorical Age (years) n(%) n 368 367 735 18-45 213 (57.9) 183 (49.9) 396 (53.9) >45-65 141(38.3) 164 (44.7) 305 (41.5) >65-75 11 (3.0) 12 (3.3) 23 (3.1) 0.131 >75 3 (0.8)  8 (2.2) 11 (1.5) Height (cm) n 368 367 735 Mean (SD) 171.33169.45 170.39 (10.020) (9.745) (9.922) Median 171.00 170.00 170.20 Min,Max 137.0, 196.9 132.1, 193.0 132.1, 0.018 196.9 Weight (kg) n 368 367735 Mean (SD) 81.62 80.15 80.89 (18.286) (19.778) (19.047) Median 79.4076.20 77.70 Min, Max 41.7, 167.0 44.5, 156.3 41.7, 167.0 0.074 BMI(kg/m{circumflex over ( )}2) n 368 367 735 Mean (SD) 27.91 27.93 27.92(6.472) (6.556) (6.510) Median 26.71 26.54 26.64 Min, Max 16.3, 71.316.7, 54.1 16.3, 71.3 0.911 Renal Function (Central Lab) n (%) n 365 363728 Normal renal function 343 (94.0) 340 (93.7) 683 (93.8) [CrCl > 80mL/min] Mild renal impairment 21 (5.8) 17 (4.7) 38 (5.2) [CrCl > 50-80mL/min] Moderate renal impairment  1 (0.3)  6 (1.7)  7 (1.0) [CrCl 30-50mL/min] Severe renal impairment 0 0 0 0.156 [CrCl < 30 mL/min] * Age iscalculated from the date of birth to the informed consent date. *p-values for differences between treatment groups are from Fisher'sexact test (for categorical variables) or Wilcoxon Rank Sum test (forcontinuous variables). * For each categorical parameter, the denominatorfor the percentage is the number of subjects who had that parameterassessed. * CrCl = Creatinine clearance

Demographic and baseline characteristics of the mITT population issummarized below:

All Omadacycline Linezolid Subjects p- Characteristics (N = 360) (N =360) (N = 720) value Gender n (%) n 360 360 720 Female 121 (33.6) 145(40.3) 266 (36.9) Male 239 (66.4) 215 (59.7) 454 (63.1) 0.076 Race n (%)n 360 360 720 White 320 (88.9) 334 (92.8) 654 (90.8) Black or African 22(6.1) 13 (3.6) 35 (4.9) American Asian  3 (0.8)  5 (1.4)  8 (1.1)American Indian or  7 (1.9)  3 (0.8) 10 (1.4) Alaska Native NativeHawaiian or  3 (0.8) 0  3 (0.4) Other Pacific Islander Other  5 (1.4)  5(1.4) 10 (1.4) 0.183 Ethnicity n (%) n 360 360 720 Hispanic or Latino148 (41.1) 151 (41.9) 299 (41.5) Not Hispanic or Latino 212 (58.9) 209(58.1) 421 (58.5) Not Reported/Unknown 0 0 0 0.880 Age (years) n 360 360720 Mean (SD) 42.7 44.5 43.6 (12.60) (13.18) (12.92) Median 41.0 45.543.0 Min, Max 18, 86 20, 84 18, 86 0.101 Categorical Age (years) n (%) n360 360 720 18-45 210 (58.3) 180 (50.0) 390 (54.2) >45-65 137 (38.1) 160(44.4) 297 (41.3) >65-75 10 (2.8) 12 (3.3) 22 (3.1) 0.123 >75  3 (0.8) 8 (2.2) 11 (1.5) Height (cm) n 360 360 720 Mean (SD) 171.38 169.43170.41 (10.103) (9.740) (9.964) Median 171.00 170.00 170.20 Min, Max137.0, 196.9 132.1, 193.0 132.1, 0.014 196.9 Weight (kg) n 360 360 720Mean (SD) 81.45 80.25 80.85 (18.233) (19.884) (19.073) Median 79.3076.60 77.70 Min, Max 41.7, 167.0 44.5, 156.3 41.7, 167.0 0.116 BMI(kg/m{circumflex over ( )}2) n 360 360 720 Mean (SD) 27.82 27.96 27.89(6.407) (6.576) (6.488) Median 26.68 26.59 26.65 Min, Max 16.3, 71.316.7, 54.1 16.3, 71.3 0.916 Renal Function (Central Lab) n (%) n 357 356713 Normal renal function 338 (94.7) 333 (93.5) 671 (94.1) [CrCl > 80mL/min] Mild renal impairment 18 (5.0) 17 (4.8) 35 (4.9) [CrCl > 50-80mL/min] Moderate renal  1 (0.3)  6 (1.7)  7 (1.0) impairment [CrCl 30-50mL/min] Severe renal 0 0 0 0.215 impairment [CrCl < 30 mL/min] * Age iscalculated from the date of birth to the informed consent date. *p-values for differences between treatment groups are from Fisher'sexact test (for categorical variables) or Wilcoxon Rank Sum test (forcontinuous variables). * For each categorical parameter, the denominatorfor the percentage is the number of subjects who had that parameterassessed. * CrCl = Creatinine clearance

The primary ABSSSI infection site at baseline in the mITT population issummarized below:

Omadacycline Linezolid (N = 360) (N = 360) Characteristics n (%) n (%)Type of Primary Infection ^([1]) 360 360 Wound Infection 210 (58.3) 214(59.4) Cellulitis/erysipelas  86 (23.9)  84 (23.3) Major Abscess  64(17.8)  62 (17.2) Location of Primary Infection 360 360 Scalp  1 (0.3) 1 (0.3) Neck  3 (0.8)  3 (0.8) Face  2 (0.6)  2 (0.6) Chest  7 (1.9)  5(1.4) Abdomen 12 (3.3) 17 (4.7) Back  6 (1.7)  8 (2.2) Groin  1 (0.3)  3(0.8) Hand 14 (3.9) 10 (2.8) Foot  7 (1.9) 13 (3.6) Shoulder 14 (3.9)  6(1.7) Buttock 33 (9.2) 37 (10.3) Axillary  8 (2.2)  6 (1.7) Arm 119(33.1) 125 (34.7) Leg 131 (36.4) 118 (32.8) Elbow  2 (0.6)  3 (0.8) Knee 1 (0.3)  4 (1.1) * Percentages are based on the number of subjects withthe specific parameter assessed. * More than one location of the primaryinfection site is recorded if the infection covers multiple sites.^([1]) Actual type of infection as reported on the eCRF.

The baseline pathogenic organisms from the ABSSSI site or blood cultureby genus and species in the micro-mITT Population are summarized below:

Omadacycline Linezolid (N = 276) (N = 287) Baseline Pathogen n (%) n (%)Gram-positive organisms (aerobes) 270 (97.8)  278 (96.9)  Staphylococcusaureus 220 (79.7)  233 (81.2)  MRSA 104 (37.7)  107 (37.3)  MSSA 120(43.5)  130 (45.3)  Staphylococcus lugdunensis 5 (1.8) 0 Streptococcuspyogenes 29 (10.5) 16 (5.6)  Streptococcus anginosus group 57 (20.7) 45(15.7) Streptococcus anginosus 27 (9.8)  20 (7.0)  Streptococcusintermedius 23 (8.3)  24 (8.4)  Streptococcus constellatus 9 (3.3) 7(2.4) Enterococcus faecalis 8 (2.9) 12 (4.2)  VRE 0 2 (0.7) VSE 7 (2.5)10 (3.5)  Enterococcus faecium 1 (0.4) 1 (0.3) VSE 1 (0.4) 1 (0.3)Streptococcus agalactiae 2 (0.7) 2 (0.7) Streptococcus mitis 1 (0.4) 0 .. . Streptococcus viridans group 3 (1.1) 0 Gram-positive organisms(anaerobes) 17 (6.2)  17 (5.9)  Clostridium perfringens 5 (1.8) 9 (3.1)Finegoldia magna 3 (1.1) 1 (0.3) . . . Gram-negative organisms (aerobes)24 (8.7)  30 (10.5)  Enterobacter aerogenes 0 1 (0.3) Enterobactercloacae 5 (1.8) 6 (2.1) Escherichia coli 4 (1.4) 1 (0.3) . . .Gram-negative organisms (anaerobes) 11 (4.0)  12 (4.2)  Prevotelladenticola 5 (1.8) 1 (0.3) Prevotella melaninogenica 2 (0.7) 3 (1.0)

In the table above, percentages were based on the number of subjects ineach treatment group. Subjects with the same pathogen isolated frommultiple specimens were counted only once for that pathogen. Subjectswith the same pathogen identified from both the blood and primary ABSSSIcultures were counted only once. MRSA and MSSA were considered distinctpathogens; VRE and VSE were considered distinct pathogens. Whenper-subject counts of Staphylococcus aureus were presented, subjectswith both MRSA and MSSA were counted only once. When per-subject countsof each Enterococcus species were presented, subjects with both VRE andVSE were counted only once. Only representative or the most abundantgenus/species were shown.

Primary Efficacy Analysis

For all efficacy analyses, subject data was analyzed in the group towhich the subject was randomized. For the primary analyses for both theFDA and EMA, subjects were analyzed in the stratum to which they wererandomized.

The Early Clinical Response could be Clinical Success, Clinical Failureand Indeterminate (defined previously). An Indeterminate Response wasincluded in the denominator for the calculation of the percentage ofsubjects with a Clinical Success in the mITT population and thus, wasessentially considered as a Clinical Failure for the purpose of theprimary analysis for the FDA.

Investigator's Assessment of Clinical Response at PTE Efficacy Variablewas defined as Investigator's Assessment of Clinical Response at the PTEvisit with outcomes of Clinical Success, Clinical Failure andIndeterminate (defined previously) in the mITT population and ClinicalSuccess and Clinical Failure in the CE population. Subjects with aresponse of Clinical Failure at EOT were defined as a Clinical Failureat PTE. An Indeterminate Response was included in the denominator forthe calculation of the percentage of subjects with a Clinical Success inthe mITT population and thus, was essentially considered a ClinicalFailure for the purpose of the primary analysis for the EMA.

To demonstrate the efficacy of omadacycline is non-inferior to linezolidin the treatment of adult subjects with ABSSSI, the following hypothesiswas evaluated by analysis of the Clinical Success rates.

The null hypothesis and alternate hypothesis for the Early ClinicalResponse endpoint were assessed in the mITT population as follows:

H _(o): θ_(T)−θ_(C)≤−Δ

H _(ai): θ_(T)−θ_(C)>−Δ

Where the clinical success rate for the omadacycline regimen is θT andfor linezolid is θC

Δ is the non-inferiority (NI) margin and is 0.10.

Similar null and alternative hypotheses can be set up with A of 0.10 forthe PTE endpoint. For the Early Clinical Response (FDA) endpoint, a2-sided 95% confidence interval (CI) approach for the difference ofclinical success rates (using the point estimate of the difference:omadacycline response proportion minus linezolid response proportion)was used to test for the NI of the omadacycline arm compared to thelinezolid arm in the mITT population. The 95% CI was calculated usingthe unstratified method proposed by Miettinen and Nurminen. Omadacyclineis considered non-inferior to linezolid if the lower bound of the CI isgreater than −0.10 (i.e., −10%).

For Investigator's Assessment of Clinical Response at PTE (EMA) primaryefficacy analyses in both the mITT and CE populations, a 2-sided 95% CIapproach for the difference of clinical success rates (using the pointestimate of the difference: omadacycline response proportion minuslinezolid response proportion) were used to test for the NI of theomadacycline arm compared to the linezolid arm. The 95% CI wascalculated using the stratified (for the randomization stratificationfactors) method proposed by Miettinen and Nurminen.

Omadacycline is considered non-inferior to linezolid if the lower boundof the CI is greater than −0.10 (i.e., −10%).

Early Clinical Response and Investigator's Assessment of ClinicalResponse at PTE were tested separately and were not co-primaryendpoints. The probability for approving an ineffective drug based onPTE efficacy is 2.5%, regardless of the result for the Early ClinicalResponse endpoint and vice versa. An adjustment would only be requiredif winning on at least 1 endpoint would result in global approval. Inaddition, no alpha adjustment is needed for the co-primary efficacyendpoints for the EMA (mITT and CE populations) since NI must be shownin both populations to conclude NI. Hence there was no adjustment formultiple endpoints.

Early clinical response at 48-72 hours after the first dose of the testarticles (Omadacycline or linezolid) in the mITT population issummarized below:

Omadacycline Linezolid (N = 360) (N = 360) Difference Efficacy Outcome n(%) n (%) (95% CI) Clinical Success 315 (87.5) 297 (82.5) 5.0 (−0.2,10.3) Clinical Failure  45 (12.5)  63 (17.5) or Indeterminate ClinicalFailure 26 (7.2) 32 (8.9) Indeterminate 19 (5.3) 31 (8.6)

In the table above, CI=Confidence Interval; Difference is observeddifference in Early Clinical Success rate between the omadacycline andlinezolid groups. 95% CI was constructed based on the Miettinen andNurminen method without stratification. Percentages were based on thenumber of subjects in each treatment group.

The early clinical success rates (at 48-72 hrs) in the mITT population,for both Omadacycline and Linezolid, are depicted in FIG. 6. See theleft most pair of bars. The data shows that the observed 5.0% differencein clinical success rate is well within the 10% margin of statisticalnon-inferiority between −0.2% and 10.3%, at 95% CI (ConfidenceInterval), and thus the primary efficacy point (for FDA approval) ismet.

Early clinical response at 48-72 hours after the first dose of the testarticles (Omadacycline or linezolid) by baseline pathogen from theABSSSI site or blood culture in the micro-mITT population is summarizedbelow:

Omadacycline Linezolid (N = 276) (N = 287) Clinical Clinical SuccessSuccess Baseline Pathogen N1 n (%) N1 n (%) Gram- positive organisms(aerobes) Staphylococcus aureus 220 194 (88.2) 233 194 (83.3) MRSA 104 97 (93.3) 107  95 (88.8) MSSA 120 101 (84.2) 130 103 (79.2)Staphylococcus lugdunensis 5  4 (80.0) 0 0 Streptococcus pyogenes 29  24(82.8) 16  13 (81.3) Streptococcus anginosus group 57  54 (94.7) 45  36(80.0) Streptococcus anginosus 27  27 (100.0) 20  17 (85.0)Streptococcus intermedius 23  21 (91.3) 24  18 (75.0) Streptococcusconstellatus 9  8 (88.9) 7   7 (100.0) Enterococcus faecalis 8  7 (87.5)12  8 (66.7) VRE 0 0 2   2 (100.0) VSE 7  6 (85.7) 10  6 (60.0)Enterococcus faecium 1   1 (100.0) 1   1 (100.0) VSE 1   1 (100.0) 1   1(100.0) Streptococcus agalactiae 2  1 (50.0) 2  1 (50.0) Streptococcusmitis 1   1 (100.0) 0 0 . . . Streptococcus viridans group 3   3 (100.0)0 0 Gram-positive organisms (anaerobes) Clostridium perfringens 5   5(100.0) 9   9 (100.0) Finegoldia magna 3  2 (66.7) 1  0 (0.0) . . .Gram- negative organisms (aerobes) Enterobacter cloacae 5   5 (100.0) 6 5 (83.3) Escherichia coli 4   4 (100.0) 1   1 (100.0) Klebsiellapneumoniae 5  4 (80.0) 6  5 (83.3) . . . Gram- negative organisms(anaerobes) Prevotella denticola 5   5 (100.0) 1   1 (100.0) Prevotellamelaninogenica 2   2 (100.0) 3   3 (100.0) . . .

In the table above, N1=Number of subjects in the micro-mITT populationin the treatment group with the baseline pathogen; n=Number of subjectsin the specific category. Percentages were based on N1. Subjects withthe same pathogen isolated from multiple specimens were counted onlyonce for that pathogen. Subjects with the same pathogen identified fromboth the blood and primary ABSSSI cultures were counted only once.Percentages were based on the number of subjects with the indicatedpathogen. Only representative or the most abundant genus/species areshown.

If the null hypothesis of inferiority is rejected for the Early ClinicalResponse in the mITT population and the observed success responseproportion for omadacycline is larger than the observed proportion forlinezolid, a formal statistical analysis of superiority is conducted. Ifthe lower limit of the 2-sided 95% CI for the treatment difference isgreater than 0%, omadacycline is considered superior to linezolid.

The primary efficacy outcome was assessed separately across thestratification factors of type of infection and receipt of allowedantibacterial therapy in the 72 hours prior to randomization stratum bytreatment group. For each type of infection stratum and each priorantibacterial therapy stratum, a 2-sided 95% CI for the observeddifference in Early Clinical Response rates was calculated for the mITTpopulation. Additional subgroup analyses of the primary efficacy outcomemay be conducted as descriptive analyses.

The results of these separate assessments across the stratificationfactors are summarized below.

Specifically, early clinical response at 48-72 hours after the firstdose of the test articles (Omadacycline or linezolid) by type ofinfection in the mITT population is summarized below:

In the table below, CI=Confidence Interval; Difference is observeddifference in Early Clinical Success rate between the omadacycline andlinezolid groups. 95% CI within each type of infection was constructedbased on the Miettinen and Nurminen method without stratification.Percentages were based on the number of subjects in each treatment groupwithin each type of infection. [1] Actual type of infection=Type ofinfection recorded on eCRF.

Type of Infection as Randomized Actual Type of Infection ^([1])Omadacycline Linezolid Omadacycline Linezolid Type of Infection (N =360) (N = 360) Difference (N = 360) (N = 360) Difference EfficacyOutcome n (%) n (%) (95% CI) n (%) n (%) (95% CI) Wound Infection 214214 6.1 (−0.6, 12.8) 210 214 6.3 (−0.3, 13.1) Clinical Success 190(88.8) 177 (82.7) 187 (89.0) 177 (82.7) Clinical Failure or  24 (11.2) 37 (17.3)  23 (11.0)  37 (17.3) Indeterminate Clinical Failure  17(7.9)  16 (7.5)  17 (8.1)  16 (7.5) Indeterminate   7 (3.3)  21 (9.8)  6 (2.9)  21 (9.8) Cellulitis/erysipelas 82 84 1.9 (−10.8, 14.5) 86 84 1.7(−10.8, 14.3) Clinical Success  65 (79.3)  65 (77.4)  68 (79.1)  65(77.4) Clinical Failure or  17 (20.7)  19 (22.6)  18 (20.9)  19 (22.6)Indeterminate Clinical Failure   8 (9.8)  12 (14.3)   8 (9.3)  12 (14.3)Indeterminate  9 (11.0)   7 (8.3)  10 (11.6)   7 (8.3) Major Abscess 6462 5.0 (−5.4, 16.2) 64 62 5.0 (−5.4, 16.2) Clinical Success  60 (93.8) 55 (88.7)  60 (93.8)  55 (88.7) Clinical Failure or   4 (6.3)  7 (11.3)  4(6.3)  7 (11.3) Indeterminate Clinical Failure   1 (1.6)   4 (6.5)  1 (1.6)   4 (6.5) Indeterminate   3 (4.7)   3 (4.8)   3 (4.7)   3(4.8)

Overall clinical response at PTE visit based on investigator assessmentsin the mITT and CE-PTE populations is summarized below:

Omadacycline Linezolid 95% CI 95% CI n (%) n (%) without with PopulationEfficacy Outcome (N = 360) (N = 360) Difference Stratification ^([1])Stratification ^([2]) mITT Clinical Success 303 (84.2) 291 (80.8) 3.3(−2.2, 8.9) (−2.2, 9.0) Clinical Failure or Indeterminate  57 (15.8)  69(19.2) Clinical Failure  12 (3.3)  21 (5.8) Indeterminate  45 (12.5)  48(13.3) CE-PTE Clinical Success (N = 284) (N = 292) 2.3 (−0.6, 5.6)(−0.5, 5.8) Clinical Failure 278 (97.9) 279 (95.5)   6 (2.1)  13 (4.5)CI = Confidence Interval; Difference is observed difference in OverallClinical Success rate at PTE between the omadacycline and linezolidgroups. ^([1]) 95% CI was constructed based on the Miettinen andNurminen method without stratification. ^([2]) 95% CI was adjusted fortype of infection and receipt of prior antibiotics based on theMiettinen and Nurminen method with stratification, usingCochran-Mantel-Haenszel weights as stratum weights. For [2], the receiptof prior antibiotic subgroups were combined into one group. Infectiontype was not combined. Overall Clinical Response at PTE was based on theInvestigator Assessment at the EOT and PTE visits. Percentages werebased on the number of subjects in each treatment group.

The overall clinical success/response rates at PTE visit based oninvestigator assessment of the mITT PTE population and the CE-PTEpopulation, for both Omadacycline and Linezolid, are also depicted inFIG. 6. See the middle (mITT PTE) and the right most (CE-PTE) pairs ofbars. The data shows that the observed 3.3% difference in overallclinical response rate in the mITT PTE population is within the 10%margin of statistical non-inferiority between −2.2% and 9.0% (withstratification), at 95% CI (Confidence Interval); and that the observed2.3% difference in overall clinical response rate in the CE-PTEpopulation is within the 10% margin of statistical non-inferioritybetween −0.5% and 5.8% (with stratification), at 95% CI (ConfidenceInterval). Thus the co-primary efficacy points (for EMA approval) arealso met.

Overall clinical response at PTE visit based on investigator assessmentsby type of infection in the mITT population is summarized below:

Type of Infection as Randomized Actual Type of Infection ^([1])Omadacycline Linezolid Omadacycline Linezolid Type of Infection (N =360) (N = 360) Difference (N = 360) (N = 360) Difference EfficacyOutcome n (%) n (%) (95% CI) n (%) n (%) (95% CI) Wound Infection 214214   6.1 (−1.6, 13.7) 210 214   5.7 (−2.0, 13.4) Clinical Success 177(82.7) 164 (76.6) 173 (82.4) 164 (76.6) Clinical Failure or  37 (17.3) 50 (23.4)  37 (17.6)  50 (23.4) Indeterminate Clinical Failure   8(3.7)  17 (7.9)   8 (3.8)  17 (7.9) Indeterminate  29 (13.6)  33 (15.4) 29 (13.8)  33 (15.4) Cellulitis/erysipelas 82 84 −5.1 (−14.9, 4.3) 8684 −4.5 (−14.0, 4.7) Clinical Success  72 (87.8)  78 (92.9)  76 (88.4) 78 (92.9) Clinical Failure or  10 (12.2)   6 (7.1)  10 (11.6)   6 (7.1)Indeterminate Clinical Failure   2 (2.4)   1 (1.2)   2 (2.3)   1 (1.2)Indeterminate   8 (9.8)   5 (6.0)   8 (9.3)   5 (6.0) Major Abscess 6462   5.3 (−8.4, 19.2) 64 62   5.3 (−8.4, 19.2) Clinical Success  54(84.4)  49 (79.0)  54 (84.4)  49 (79.0) Clinical Failure or  10 (15.6) 13 (21.0)  10 (15.6)  13 (21.0) Indeterminate Clinical Failure   2(3.1)   3 (4.8)   2 (3.1)   3 (4.8) Indeterminate  8 (12.5)  10 (16.1) 8 (12.5)  10 (16.1) CI = Confidence Interval; Difference is observeddifference in Overall Clinical Success rate at PTE between theomadacycline and linezolid groups. 95% CI within each type of infectionwas constructed based on the Miettinen and Nurminen method withoutstratification. Percentages were based on the number of subjects in eachtreatment group within each type of infection. ^([1]) Actual type ofinfection = Type of infection recorded on eCRF.

Overall clinical success at PTE visit based on investigators assessmentby baseline pathogen from the ABSSSI site or blood culture micro-mITTpopulation is summarized below:

Omadacycline Linezolid (N = 276) (N = 287) Clinical Clinical SuccessSuccess Baseline Pathogen N1 n (%) N1 n (%) Gram-positive organisms(aerobes) Staphylococcus aureus 220 182 (82.7)  233 186 (79.8)  MRSA 10489 (85.6) 107 85 (79.4) MSSA 120 97 (80.8) 130 103 (79.2) Staphylococcus lugdunensis 5  4 (80.0) 0 0 Streptococcus pyogenes 29 20(69.0) 16  9 (56.3) Streptococcus anginosus 57 49 (86.0) 45 33 (73.3)group Streptococcus anginosus 27 24 (88.9) 20 16 (80.0) Streptococcusintermedius 23 18 (78.3) 24 16 (66.7) Streptococcus constellatus 9  8(88.9) 7  5 (71.4) Enterococcus faecalis 8  8 (100.0) 12  9 (75.0) VRE 00 2  2 (100.0) VSE 7  7 (100.0) 10  7 (70.0) Enterococcus faecium 1  1(100.0) 1  1 (100.0) VSE 1  1 (100.0) 1  1 (100.0) Streptococcusagalactiae 2  1 (50.0) 2  1 (50.0) Streptococcus mitis 1  1 (100.0) 0 0. . . Streptococcus viridans group 3  3 (100.0) 0 0 Gram-positiveorganisms (anaerobes) Clostridium perfringens 5  4 (80.0) 9  7 (77.8)Finegoldia magna 3  3 (100.0) 1 0 (0.0) . . . Gram-negative organisms(aerobes) Enterobacter cloacae 5  4 (80.0) 6  6 (100.0) Escherichia coli4  4 (100.0) 1  1 (100.0) Klebsiella pneumoniae 5  4 (80.0) 6  4 (66.7). . . Gram-negative organisms (anaerobes) Prevotella denticola 5  3(60.0) 1 0 (0.0) Prevotella melaninogenica 2  2 (100.0) 3  3 (100.0) . .. N1 = Number of subjects in the micro-mITT population in the treatmentgroup with the baseline pathogen. n = Number of subjects in the specificcategory. Percentages were based on N1. Subjects with the same pathogenisolated from multiple specimens were counted only once for thatpathogen. Subjects with the same pathogen identified from both the bloodand primary ABSSSI cultures were counted only once. Percentages werebased on the number of subjects in each treatment group having theindicated pathogen.

Additional and sensitivity analyses of the primary efficacy outcomes(Early Clinical Response and Investigator's Assessment of ClinicalResponse at PTE) were performed (data not shown). Sensitivity analysesincluded: conducting an adjusted analysis of the primary efficacyoutcome based on the randomized stratum and separately, based on thestratum the subject actually belongs, and conducting an analysis whereall subjects with an Indeterminate response are considered ClinicalSuccesses.

Secondary Efficacy Analysis

The number and percentage of subjects classified as a Clinical Success,Clinical Failure and Indeterminate by the Investigator's Assessment atPTE in the mITT and CE populations (by definition subjects with anIndeterminate response were excluded from the CE population) werecalculated for each treatment group. A 2-sided unadjusted 95% CI wasconstructed for the observed difference in the clinical success rateusing the method of Miettinen and Nurminen. For Investigator'sAssessment of Clinical Response at PTE in the mITT and CE populationsthe 2-sided 95% CI was for descriptive purposes only and no conclusionof NI was made.

The number and percentage of subjects in each treatment group in eachresponse category for Early Clinical Response were presented for themicro-mITT population. The number and percentage of subjects who wereclassified as a Clinical Success and Clinical Failure by theinvestigator at the PTE visit in the ME population were calculated.Two-sided unadjusted 95% CI was constructed for the observed differencein the clinical success rates using the method of Miettinen andNurminen.

The number and percentage of subjects with an Early Clinical Response ofsuccess and an Investigator's Assessment of Clinical Response at PTE ofClinical Success by pathogen (including Gram-negative causativepathogens and MRSA) were provided in the micro-mITT and ME populations.

Analysis of Additional Efficacy Variables

Additional efficacy analyses were conducted to support the efficacyfindings of the primary and secondary outcomes. CIs were determined fordescriptive purposes, but no conclusions of NI were made.

The number and percentage of subjects classified as an Early ClinicalSuccess, Clinical Failure and Indeterminate at 48 to 72 hours after thefirst dose of test article in the ITT population were calculated. A2-sided unadjusted 95% CI was constructed for the observed difference inthe Clinical Success rate using the method of Miettinen and Nurminen.

The number and percentage of subjects classified as a Clinical Success,Clinical Failure and Indeterminate by the Investigator's Assessment atEOT in the mITT and CE populations (by definition subjects with anIndeterminate response were excluded from the CE population) werecalculated for each treatment group. A 2-sided unadjusted 95% CI wasconstructed for the observed difference in the clinical success rateusing the method of Miettinen and Nurminen.

Descriptive summaries, including change from baseline where appropriate,of the clinical signs and symptoms (tenderness, edema, erythema,induration and drainage), complete resolution of the clinical signs andsymptoms, temperature, ABSSSI lesion measurements (including absoluteand percentage reduction in lesion area, e.g., 0 to <5%, 5 to <10%, 10to <20%, ≥20%, etc.), and systemic signs by study visit were presented.

All-cause mortality (ACM) at 15 and 30 days after the first dose of testarticle was summarized in the ITT population. Subjects who were lost tofollow-up are considered deceased for this analysis. A 2-sidedunadjusted 95% CI for the observed difference in mortality rates wascalculated for ACM.

The per-subject and per-pathogen microbiologic outcomes were providedfor the micro-mITT and ME populations at the EOT and PTE visits.Two-sided unadjusted 95% CIs were provided for the difference inper-subject microbiological favorable outcome rates.

A concordance analysis of Early Clinical Response and Investigator'sAssessment of Clinical Response at PTE in the mITT analysis set werepresented.

Safety Outcome Measures

Safety variables include the incidence rate of AEs, change in vitalsigns, ECG parameters and laboratory test results obtained during thecourse of the study. For safety analyses, subjects were analyzedaccording to the treatment actually received.

Summary tables were provided for all treatment-emergent adverse events(TEAEs). A TEAE is defined as an AE with a start date and time on orafter the first dose of test article. AEs were coded using the MedicalDictionary for Regulatory Activities (MedDRA) and were summarized bypresenting the number and percentage of subjects having each TEAE foreach treatment group by system organ class (SOC) and preferred term(PT). Additional tabulations provide summaries by SOC and PT of subjectsexperiencing SAEs, severe TEAEs, TEAEs judged to be related to testarticle, TEAEs leading to discontinuation of test article, and TEAEs ofspecial interest.

An overview of the AEs in the safety population is provided below:

Omadacycline Linezolid (N = 368) (N = 367) Parameter n (%) n (%) TotalNumber of AEs 468 250 Total Number of TEAEs 448 239 Subjects with atLeast One, n (%) Adverse Events (AE) 201 (54.6) 140 (38.1) TEAE 197(53.5) 137 (37.3) Drug-Related TEAE 139 (37.8)  52 (14.2) Severe TEAE  6(1.6)  7 (1.9) Serious TEAE  5 (1.4)  5 (1.4) Drug-Related Serious TEAE0  1 (0.3) Serious TEAE leading to Death 0  1 (0.3) TEAE leading topremature  6 (1.6)  3 (0.8) discontinuation of test article TEAE leadingto premature  3 (0.8)  1 (0.3) discontinuation of study TEAE leading todose interruption 0 0 Serious TEAEs leading to premature  3 (0.8)  2(0.5) discontinuation of test article Subjects who died, n (%) 0  1(0.3) Percentages were based on the Safety population. A TEAE is definedas an AE occurring after first dose of active test article.

A summary of treatment-emergent adverse events (TEAEs) leading to studydrug discontinuation by system organ class and preferred term in thesafety population is provided below:

Omadacycline Linezolid System Organ Class (SOC) (N = 368) (N = 367)Preferred Term (PT) n (%) n (%) Subjects with at Least One TEAE 6 (1.6)3 (0.8) Leading to Study Drug Discontinuation Gastrointestinal Disorders1 (0.3) 0 Haematemesis 1 (0.3) 0 Nausea 1 (0.3) 0 Vomiting 1 (0.3) 0Infections And Infestations 4 (1.1) 1 (0.3) Wound Infection 1 (0.3) 1(0.3) Cellulitis 1 (0.3) 0 Staphylococcal Bacteraemia 1 (0.3) 0Subcutaneous Abscess 1 (0.3) 0 Pregnancy, Puerperium And Perinatal 1(0.3) 0 Conditions Pregnancy 1 (0.3) 0 Coding of system organ class andpreferred term was based on MedDRA Version 17.1. Percentages were basedon the Safety population. A TEAE is defined as an AE occurring afterfirst dose of active test article. If a subject had more than one TEAEthat coded to the same MedDRA category, the subject was counted onlyonce.

A summary of the most frequent (≥2%) treatment-emergent adverse events(TEAEs) by preferred term in the safety population is provided below:

Omadacycline Linezolid (N = 368) (N = 367) Preferred Term (PT) n (%) n(%) Subjects with at Least One TEAE 197 (53.5) 137 (37.3) Nausea 111(30.2) 28 (7.6) Vomiting  62 (16.8) 11 (3.0) Wound Infection 22 (6.0) 17(4.6) Alanine Aminotransferase Increased 19 (5.2) 11 (3.0) AspartateAminotransferase Increased 17 (4.6) 12 (3.3) Diarrhea 15 (4.1) 10 (2.7)Headache 13 (3.5)  8 (2.2) Cellulitis 12 (3.3)  9 (2.5) Abdominal PainUpper 10 (2.7)  4 (1.1) . . . Coding of preferred term was based onMedDRA Version 17.1. Percentages were based on the safety population. ATEAE was defined as an AE occurring after first dose of active testarticle. If a subject had more than one TEAE that coded to the sameMedDRA category, the subject was counted only once.

A summary of the most frequent GI treatment-emergent adverse events(TEAEs) in the safety population is provided below:

Omadacycline (N = 368) Linezolid (N = 367) System Organ Class (SOC) MildModerate Severe Mild Moderate Severe Preferred Term (PT) n (%) n (%) n(%) n (%) n(%) n (%) Subjects with at Least One TEAE 120 (32.6) 71(19.3) 6 (1.6) 85 (23.2) 45 (12.3) 7(1.9) Gastrointestinal Disorders 105(28.5) 39 (10.6) 0 44 (12.0)  8 (2.2) 0 Nausea  83 (22.6)  28 (7.6) 0 24 (6.5)  4 (1.1) 0 Vomiting  44 (12.0)  18 (4.9) 0  10 (2.7)  1 (0.3)0 Abdominal Pain   3 (0.8)  3 (0.8) 0  1 (0.3)  1 (0.3) 0 Diarrhea  13(3.5)  2 (0.5) 0  9 (2.5)  1 (0.3) 0 Abdominal Pain Upper   9 (2.4)  1(0.3) 0  4 (1.1) 0 0 Coding of system organ class and preferred term wasbased on McdDRA Version 17.1. Percentages were based on the Safetypopulation. A TEAE was defined as an AE occurring after first dose ofactive test article. If a subject had more than one TEAE that coded tothe same MedDRA category, the subject was counted only once at thehighest severity. TEAEs with missing severity were not displayed.

The following variables were analyzed descriptively: Vital signs(systolic and diastolic BP, pulse rate, body temperature, respiratoryrate), including change from Screening by visit; Clinically notablevital signs (meeting predefined criteria as specified in the SAP) byvisit. Subjects with notable vital signs data were listed.

ECG data (RR interval, PR interval, QRS interval, QTc, QTc Bazett'sCorrection Formula [QTcB], and QTc Fridericia's Correction Formula[QTcF]) was summarized descriptively at each scheduled evaluation, andfor the overall worst post-Screening value. Changes from Screening ateach visit that a 12-lead ECG was obtained was also provided. An outlieranalysis was conducted based on the worst post-Screening value.

The following variables were analyzed descriptively: Laboratoryvariables by visit; Change from Screening of laboratory variables byvisit; and Clinically notable laboratory values (meeting predefinedcriteria specified in the SAP) by visit.

Listings of individual subject laboratory data were generated. Valuesmeeting predefined criteria for being clinically notable were flaggedwithin the listings.

Pharmacokinetics Population PK analysis was conducted to characterize PKparameters. A population PK data set including subjects with 1 or morequantified omadacycline concentration determinations are constructedfrom the dates and times of the doses and blood samples along with allthe bioanalytical determinations and subject background information. Ifthe actual date or time for a blood sample or dose was missing, therelated bioanalytical determination of the PK concentration was excludedfrom all analyses. Omadacycline concentrations below the limit ofquantification were treated as missing data in summary statistics andfor the calculation of PK parameters.

Variables including age (years), body weight (kg), gender, andrace/ethnicity along with other covariates previously determined to beimportant were incorporated into the population PK database. Based onthe subjects in the population analysis data set, descriptive summariesat Screening for these variables were reported. Outliers may be excludedfrom the analysis. These were determined by a scatter plot of theobserved concentration versus time post dose reported. The distributionof the number of samples contributed per subject to the model-basedanalysis was tabulated. Also, simple summary descriptive statistics forthe concentration of samples by study day or week were computed.

Concerning population PK modeling, results from Phase 1 studiesindicated that omadacycline PK was linear and that following intravenousinfusion, plasma concentration-time profiles show a 3-compartmentaldisposition. Therefore, the probable structural PK model would be a3-compartment model with zero order input for i.v. infusion and firstorder input for p.o. administration. This PK model contains theparameters clearance, volume of distribution, bioavailability andabsorption rate constant. The associated population models are nonlinearmixed-effects models. The population model adds random effects andcovariates for the PK parameters in order to recognize differences amongindividuals and similarities across observations corresponding to thesame subject. At the time of the population modeling, previouslyreported structural PK models will be considered first. A residual errormodel combining additive error and proportional error is initiallyconsidered. Simplifications (e.g., fewer random affects or analternative residual error model) may be appropriate if the diagnosticsfor the model suggest false convergence. Additional covariates areinvestigated graphically (gender, race/ethnicity, age) as part of themodel diagnostics and some may be retained in the final model andadditional ones in a competing model to deliver estimates of arguablyinsignificant effects. Scatter plots of the observed concentrationsversus population-estimated and individually estimated concentrationsare used as part of the overall assessment of the overall quality of thefit. During modeling, the broad principles outlined by the FDA arefollowed.

The individual model-based exposure measures at steady state (area underthe curve [AUC]₀₋₂₄,ss, time to maximum plasma concentration[T_(max),ss], maximum plasma concentration [C_(max),ss]) are computedand summarized.

The relationship between omadacycline exposure and response (efficacyand safety) will be examined as appropriate for the data. A populationPK model will be used to calculate individual subject AUCs and,subsequently, possible AUC/MIC breakpoints.

1-10. (canceled)
 11. A method of treating a human subject in need oftreatment for a bacterial skin or skin structure infection, comprisingorally administering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450mg per day for two consecutive days, then at a dose of about 300 mg perday for 5 or more days, wherein said bacterial skin or skin structureinfection is known or suspected to be caused by Gram-positive pathogens.12-16. (canceled)
 17. A method of treating a human subject in need oftreatment for a bacterial skin or skin structure infection, comprisingorally administering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450mg per day for two consecutive days, then at a dose of about 300 mg perday for 5 or more days, wherein said bacterial skin or skin structureinfection is a result of vascular insufficiency or edema.
 18. (canceled)19. A method of treating a human subject in need of treatment for abacterial skin or skin structure infection, comprising orallyadministering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450mg per day for two consecutive days, then at a dose of about 300 mg perday for 5 or more days, wherein each oral dose of said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered about24 hours apart. 20-21. (canceled)
 22. A method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising orally administering to said subject an effectiveamount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a saltthereof, such that said subject is treated, wherein said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredorally at a dose of about 450 mg per day for two consecutive days, thenat a dose of about 300 mg per day for 5 or more days, wherein saidsubject is treated for 8 days. 23-25. (canceled)
 26. The method of claim11, wherein said Gram-positive pathogens include Staphylococcus aureusthat is methicillin-resistant Staphylococcus aureus (MRSA), ormethicillin-susceptible Staphylococcus aureus (MSSA).
 27. The method ofclaim 11, wherein said Gram-positive pathogens include Streptococcusspecies that include Streptococcus anginosus group.
 28. The method ofclaim 11, wherein said Gram-positive pathogens include Streptococcusspecies that include beta-hemolytic Streptococci or S. anginosus. 29.The method of claim 11, wherein said Gram-positive pathogens includeStreptococcus species that include non-hemolytic Streptococci or S.intermedius.
 30. The method of claim 11, wherein said Gram-positivepathogens include Streptococcus species that include alpha-hemolyticStreptococci or S. constellatus.
 31. The method of claim 11, whereinsaid Gram-positive pathogens include Enterococcus species that includeEnterococcus faecalis (VSE).
 32. The method of claim 11, wherein saidGram-positive pathogens include Streptococcus species that includeStreptococcus pyogenes.
 33. A method of treating a human subject in needof treatment for a bacterial skin or skin structure infection,comprising orally administering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450mg per day for two consecutive days, then at a dose of about 300 mg perday for 5 or more days, wherein said bacterial skin or skin structureinfection is known or suspected to be caused by Gram-negative pathogens.34. (canceled)
 35. A method of treating a human subject in need oftreatment for a bacterial skin or skin structure infection, comprisingorally administering to said subject an effective amount of9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof,such that said subject is treated, wherein said 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450mg per day for two consecutive days, then at a dose of about 300 mg perday for 5 or more days, wherein GI adverse events (AEs) associated withtreatment are predominantly mild.
 36. A method of treating a humansubject in need of treatment for a bacterial skin or skin structureinfection, comprising orally administering to said subject an effectiveamount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a saltthereof, such that said subject is treated, wherein said9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administeredorally at a dose of about 450 mg per day for two consecutive days, thenat a dose of about 300 mg per day for 5 or more days, wherein GI adverseevents (AEs) associated with treatment do not result in discontinuationof therapy. 37-48. (canceled)